IL323873A

IL323873A - Trem compositions and methods of use

Info

Publication number: IL323873A
Application number: IL323873A
Authority: IL
Original assignee: Flagship Pioneering Innovations Vi Llc
Priority date: 2023-04-12
Filing date: 2025-10-09
Publication date: 2025-12-01
Also published as: WO2024216206A2; WO2024216206A3; KR20250171374A; CN121241138A; EP4695392A2; AU2024249959A1; TW202507003A

Description

WO 2024/216206 PCT/US2024/024492 TREM COMPOSITIONS AND METHODS OF USE CLAIM OF PRIORITY This application claims priority to U.S. Provisional Application No. 63/458,891, filed on April 12, 2023; U.S. Provisional Application No. 63/458,894, filed on April 12, 2023; and U.S. Provisional Application No. 63/458,911, filed on April 12, 2023. The entire contents of each of the foregoing applications are incorporated herein by reference in their entirety.

BACKGROUNDTransfer RNAs (tRNAs) are complex, naturally occurring RNA molecules that possess a number of functions including initiation and elongation of proteins.

SUMMARYThe present disclosure features modified tRNA-based effector molecules (TREMs, e.g., a TREM or TREM fragment), as well as related compositions and uses thereof. TREMs are complex molecules which can mediate a variety of cellular processes. For example, the TREMs described herein may have the ability to: (i) support protein synthesis, (ii) be charged by a tRNA synthetase, (iii) be bound by an elongation factor, (iv) introduce an amino acid into a peptide chain, (v) support protein elongation, or (vi) support initiation of protein synthesis, e.g., in a cell.Described herein are TREMs and related methods for optimizing the nucleotide sequence of a TREM, e.g., to improve a functional parameter of a TREM, e.g., to increase TREM stability. For example, the methods provided show that the nucleotide sequence of a TREM may be modified, e.g., by a substituting one nucleotide for another, to modulate a functional parameter of a TREM, for example to achieve an improvement in a functional parameter of a TREM. In an embodiment, the TREMs disclosed herein comprise at least one chemical modification (e.g., a non-naturally occurring modification), e.g., on a component nucleotide (e.g., a nucleobase or sugar) or within an internucleotide region, e.g., the TREM backbone. In another embodiment, the TREMs disclosed herein do not comprise a chemical modification (e.g., a non-naturally occurring modification), e.g., on a component nucleotide (e.g., a nucleobase or sugar) or within an internucleotide region, e.g., the TREM backbone). The present disclosure provides methods for tuning a functional parameter of a TREM by optimizing the nucleotide sequence, WO 2024/216206 PCT/US2024/024492 demonstrating a nucleotide sequence substitution (e.g., or further comprises a non-naturally occurring modification) may modulate a functional parameter of a TREM.In one aspect, provided herein is a TREM comprising a sequence of Formula (A): [Ll]x- [ASt Domainl]-[L2]x-[DH Domain]-[L3]x-[ACH Domain]-[VL Domain]-[TH D0main]-[L4]x- [ASt Domain2]-[L5]x, wherein independently, [El] and [VL Domain], are optional; x, independently for every occurrence, is 0 or 1; and one of [Li], [ASt Domainl], [L2]-[DH Domain], [L3], [ACH Domain], [VL Domain], [TH Domain], [L4], and [ASt Domain2] comprises a nucleotide substitution relative to a reference sequence (e.g., a second TREM), wherein the TREM comprises a nucleotide substitution (e.g., a nucleotide mutation) in the TREM capable of modulating a functional parameter of the TREM. In an embodiment, a TREM described herein comprises a plurality of nucleotide substitutions (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, or 80, e.g., relative to a reference sequence).In another aspect, provided herein is a TREM comprising a sequence of Formula (A): [Ll]x-[ASt Domainl]-[L2]x-[DH Domain]-[L3]x-[ACH Domain]-[VL Domain]-[TH Domain]- [L4]x-[AStDomain2]-[L5]x, wherein independently, [Li] and [VL Domain], are optional; x, independently for every occurrence, is 0 or 1; and one of [Li], [ASt Domainl], [L2]-[DH Domain], [L3], [ACH Domain], [VL Domain], [TH Domain], [L4], and [ASt Domain2] comprises a nucleotide comprising a non-naturally occurring modification. In an embodiment, a TREM described herein comprises at least X contiguous nucleotides without a non-naturally occurring modification, wherein X is greater than 3, 4, 5, 6, 7, 8, 9, or 10; comprises at least 3, but less than all of the nucleotides of a type (e.g., A, T, C, G or U) comprise the same non- naturally occurring modification; comprises at least X nucleotides of a type (e.g., A, T, C, G or U) that do not comprise a non-naturally occurring modification, wherein X= than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56,58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, or 80; comprises no more than 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60,62, 64, 66, 68, 70, 72, 74, 76, 78, or 80 nucleotides of a type (e.g., A, T, C, G or U) that comprisea non-naturally occurring modification; and/or comprises no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, WO 2024/216206 PCT/US2024/024492 64, 66, 68, 70, 72, 74, 76, 78, or 80 nucleotides of a type (e.g., A, T, C, G or U) that do not comprise a non-naturally occurring modification.In an embodiment, the TREM Domain comprising the non-naturally occurring modification has a function, e.g., a domain function described herein.In an aspect, provided herein is a TREM core fragment comprising a sequence of Formula B:[Li] y -[ASt Domain 1 ] X-[L2] y -[DH Domain] y -[L3] y -[ACH Domain] x -[VL Domain] y -[TH Domain] y -[L4] y -[ASt Domain2] x ,wherein x=l and y=0 or 1; and one of [ASt Domain 1], [ACH Domain], and [ASt Domain2] comprises a nucleotide having a non-naturally occurring modification.In an embodiment, the TREM has the ability to support protein synthesis. In an embodiment, the TREM has the ability to be able to be charged by a synthetase. In an embodiment, the TREM has the ability to be bound by an elongation factor. In an embodiment, the TREM has the ability to introduce an amino acid into a peptide chain. In an embodiment, the TREM has the ability to support elongation. In an embodiment, the TREM has the ability to support initiation.In an embodiment, the [ASt Domain 1] and/or [ASt Domain 2] comprising the non- naturally occurring modification has the ability to initiate or elongate a polypeptide chain.In an embodiment, the [ACH Domain] comprising the non-naturally occurring modification has the ability to mediate pairing with a codon.In an embodiment, y=l for any one, two, three, four, five, six, all or a combination of [LI], [L2], [DH Domain], [L3], [VL Domain], [TH Domain], [L4].In an embodiment, y=0 for any one, two, three, four, five, six, all or a combination of [LI], [L2], [DH Domain], [L3], [VL Domain], [TH Domain], [L4].In an embodiment, y=l for linker [Li], and Li comprises a nucleotide having a non- naturally occurring modification.In an embodiment, y=l for linker [L2], and L2 comprises a nucleotide having a non- naturally occurring modification.In an embodiment, y=l for [DH Domain (DHD)], and DHD comprises a nucleotide having a non-naturally occurring modification. In an embodiment, the DHD comprising the non- WO 2024/216206 PCT/US2024/024492 naturally occurring modification has the ability to mediate recognition of aminoacyl-tRN A synthetase.In an embodiment, y=l for linker [L3], and L3 comprises a nucleotide having a non- naturally occurring modification.In an embodiment, y=l for [VL Domain (VLD)], and VLD comprises a nucleotide having a non-naturally occurring modification.In an embodiment, y=l for [TH Domain (THD)], and THD comprises a nucleotide having a non-naturally occurring modification. In an embodiment, the THD comprising the non- naturally occurring modification has the ability to mediate recognition of the ribosome.In an embodiment, y=l for linker [L4], and L4 comprises a nucleotide having a non- naturally occurring modification.In another aspect, the disclosure provides a TREM fragment comprising a portion of a TREM, wherein the TREM comprises a sequence of Formula A:[Ll]-[ASt Domain 1]-[L2]-[DH Domain]-[L3]-[ACH Domain] -[VL Domain]-[TH D0main]-[L4]-[ASt Domain2], and wherein the TREM fragment comprises a non-naturally occurring modification.In an embodiment, the TREM fragment comprises one, two, three or all or any combination of the following: (a) a TREM half (e.g., from a cleavage in the ACH Domain, e.g., in the anticodon sequence, e.g., a 5’half or a 3’ half); (b) a 5’ fragment (e.g., a fragment comprising the 5’ end, e.g., from a cleavage in a DH Domain or the ACH Domain); (c) a 3’ fragment (e.g., a fragment comprising the 3’ end, e.g., from a cleavage in the TH Domain); or (d) an internal fragment (e.g., from a cleavage in any one of the ACH Domain, DH Domain or TH Domain).In an embodiment, the TREM fragment comprise (a) a TREM half which comprises a nucleotide having a non-naturally occurring modification.In an embodiment, the TREM fragment comprise (b) a 5’ fragment which comprises a nucleotide having a non-naturally occurring modification.In an embodiment, the TREM fragment comprise (c) a 3’ fragment which comprises a nucleotide having a non-naturally occurring modification.In an embodiment, the TREM fragment comprise (d) an internal fragment which comprises a nucleotide having a non-naturally occurring modification.

WO 2024/216206 PCT/US2024/024492 In an embodiment of any of the TREMs, TREM core fragments, or TREM fragments disclosed herein, the TREM Domain comprises a plurality of nucleotides each having a non- naturally occurring modification. In an embodiment, the non-naturally occurring modification comprises a nucleobase modification, a sugar (e.g., ribose) modification, or a backbone modification. In an embodiment, the non-naturally occurring modification is a sugar (e.g., ribose) modification. In an embodiment, the non-naturally occurring modification is 2’-ribose modification, e.g., a 2’-OMe, 2’-halo (e.g., 2’-F), 2’-M0E, or 2’-deoxy modification. In an embodiment, the non-naturally occurring modification is a backbone modification, e.g., a phosphorothioate modification.In an embodiment of any of the TREMs, TREM core fragments, or TREM fragments disclosed herein, the TREM sequence comprises a CCA sequence on a terminus, e.g., the 3’ terminus. In an embodiment, the TREM sequence does not comprise a CCA sequence on a terminus, e.g., the 3’ terminus.In an embodiment of any of the TREMs, TREM core fragments, or TREM fragments disclosed herein, the non-naturally occurring modification is a modification in a base or a backbone of a nucleotide, e.g., a modification chosen from any one of Tables 5, 6, 7, 8 or or 9.In an embodiment of any of the TREMs, TREM core fragments, or TREM fragments disclosed herein, the non-naturally occurring modification is a base modification chosen from a modification listed in Table 5.In an embodiment of any of the TREMs, TREM core fragments, or TREM fragments disclosed herein, the TREM, TREM core fragment, or TREM fragment is encoded by a sequence provided in Table 1, e.g., any one of SEQ ID NOs 1-451.In an embodiment of any of the TREMs, TREM core fragments, or TREM fragments disclosed herein, the TREM, TREM core fragment, or TREM fragment is encoded by a consensus sequence chosen from any one of SEQ ID NOs: 562-621.In an embodiment of any of the TREMs, TREM core fragments, or TREM fragments disclosed herein, the TREM, TREM core fragment, or TREM fragment is encoded by a sequence provided in FIG. 3, e.g., any one of SEQ ID NOs: 625-1151. In an embodiment, the TREM, TREM core fragment, or TREM fragment comprises a TREM having at least 70%, 75%, 80%, 85%, 90%, 95%, or 99% sequence identity with a TREM provided in FIG. 3, e.g., any one of SEQ ID NOs: 625-1151. In an embodiment, the TREM, TREM core fragment, or TREM WO 2024/216206 PCT/US2024/024492 fragment comprises a sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, or nucleotides from a TREM provided in FIG. 3, e.g., any one of SEQ ID NOs: 625-1151. In an embodiment, the TREM, TREM core fragment, or TREM fragment comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 additional non-naturally occurring modifications compared with a TREM, TREM core fragment, or TREM fragment provided in FIG. 3, (e.g., 2’-ribose modifications or an internucleotide modification, e.g., 2’OMe, 2’-halo, 2’-MOE, 2’-deoxy, or phosphorothiorate modifications), e.g., any one of SEQ ID NOs: 625-1151.In an embodiment of any of the TREMs, TREM core fragments, or TREM fragments disclosed herein, the TREM, TREM core fragment, or TREM fragment is a TREM provided in FIG. 3, e.g., any one of SEQ ID NOs: 625-1151. In an embodiment, the TREM, TREM core fragment, or TREM fragment comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 additional non-naturally occurring modifications compared with a TREM provided in FIG. 3 (e.g., 2’-ribose modifications or an internucleotide modification, e.g., 2’0Me, 2’-halo, 2’-MOE, 2’-deoxy, or phosphorothiorate modifications), e.g., any one of SEQ ID NOs. 625-1151.In another aspect, the disclosure provides a pharmaceutical composition comprising a TREM, a TREM core fragment, or a TREM fragment disclosed herein.In another aspect, a TREM or a related composition thereof can be used, inter alia, to modulate a functional parameter (e.g., an expression parameter and/or a signaling parameter) of an RNA corresponding to, or a polypeptide encoded by, a nucleic acid sequence comprising an endogenous open reading frame (ORF) having a premature termination codon (PTC).In another aspect, provided herein is a method of modulating a functional parameter of an mRNA corresponding to, or polypeptide encoded by, an endogenous open reading frame (ORF) in a subject, which ORF comprises a premature termination codon (PTC), contacting the subject with a TREM composition comprising a TREM, a TREM core fragment, or a TREM fragment disclosed herein in an amount and/or for a time sufficient to modulate the functional parameter of the mRNA or polypeptide, wherein the TREM, TREM core fragment or TREM fragment has an anticodon that pairs with the codon having the first sequence, thereby modulating the functional parameter in the subject. In an embodiment, the functional parameter comprises a signaling parameter and/or an expression parameter, e.g., as described herein.In another aspect, disclosed herein is a method of modulating expression of a protein in a cell, wherein the protein is encoded by a nucleic acid comprising an endogenous open reading WO 2024/216206 PCT/US2024/024492 frame (ORF), which ORF comprises a premature termination codon (PTC), comprising contacting the cell with a TREM composition comprising a TREM, a TREM core fragment, or a TREM fragment disclosed herein in an amount and/or for a time sufficient to modulate expression of the encoded protein, wherein the TREM, TREM core fragment or TREM fragment has an anticodon that pairs with the PTC, thereby modulating expression of the protein in the cell. In an embodiment, the PTC comprises UAA, UGA or UAG.In another aspect, provided herein is a method of increasing expression of a protein in a subject wherein the protein is encoded by a nucleic acid comprising an endogenous open reading frame (ORF), which ORF comprises a premature termination codon (PTC), comprising contacting the subject, in an amount and/or for a time sufficient to increase expression of the protein, with a TREM composition that (i) has an anticodon that pairs with the PTC, (ii) recognizes an aminoacyl-tRNA synthetase specific for Trp, Tyr, Cys, Glu, Lys, Gin, Ser, Leu, Arg, or Gly, (iii) comprises a sequence of Formula A, or (iv) comprises a non-naturally occurring modification. In an embodiment, the PTC comprises UAA, UGA or UAG. In an embodiment, the TREM composition comprises (i). In an embodiment, the TREM composition comprises (ii). In an embodiment, the TREM composition comprises (iii). In an embodiment, the TREM composition comprises (iv). In an embodiment, the TREM composition comprises two of (i)- (iv). In an embodiment, the TREM composition comprises three of (i)-(iv). In an embodiment, the TREM composition comprises each of (i)-(iv).In another aspect, the disclosure provides a method of treating a subject having an endogenous open reading frame (ORF) which comprises a premature termination codon (PTC), comprising providing a TREM composition comprising a TREM, a TREM core fragment, or a TREM fragment disclosed herein, wherein the TREM comprises an anticodon that pairs with the PTC in the ORF; contacting the subject with the composition comprising a TREM, TREM core fragment or TREM fragment in an amount and/or for a time sufficient to treat the subject, thereby treating the subject. In an embodiment, the PTC comprises UAA, UGA or UAG.In another aspect, the disclosure provides a method of treating a subject having an disease or disorder associated with a premature termination codon (PTC), comprising providing a TREM composition comprising a TREM, a TREM core fragment, or a TREM fragment disclosed herein; contacting the subject with the composition comprising a TREM, TREM core fragment or TREM fragment in an amount and/or for a time sufficient to treat the subject, thereby treating WO 2024/216206 PCT/US2024/024492 the subject. In an embodiment, the PTC comprises UAA, UGA or UAG. In an embodiment, the disease or disorder associated with a PTC is a disease or disorcer described herein, e.g., a cancer or a monogenic disease.In an embodiment of any of the methods disclosed herein, the codon having the first sequence comprises a mutation (e.g., a point mutation, e.g., a nonsense mutation), resulting in a premature termination codon (PTC) chosen from UAA, UGA or UAG. In an embodiment, the codon having the first sequence or the PTC comprises a UAA mutation. In an embodiment, thecodon having the first sequence or the PTC comprises a UGA mutation. In an embodiment, thecodon having the first sequence or the PTC comprises a UAG mutationIn another aspect, the disclosure provides a method of making a TREM, a TREM core fragment, or a TREM fragment disclosed herein, comprising linking a first nucleotide to a second nucleotide to form the TREM.In an embodiment, the TREM, TREM core fragment or TREM fragment is non-naturally occurring (e.g., synthetic).In an embodiment, the TREM, TREM core fragment or TREM fragment is made by cell- free solid phase synthesis.In another aspect, the disclosure provides a method of modulating a tRNA pool in a cell comprising: providing a TREM, a TREM core fragment, or a TREM fragment disclosed herein, and contacting the cell with the TREM, TREM core fragment or TREM fragment, thereby modulating the tRNA pool in the cell.In an aspect, the disclosure provides a method of contacting a cell, tissue, or subject with a TREM, a TREM core fragment, or a TREM fragment disclosed herein, comprising: contacting the cell, tissue or subject with the TREM, TREM core fragment or TREM fragment, thereby contacting the cell, tissue, or subject with the TREM, TREM core fragment or TREM fragment.In another aspect, the disclosure provides a method of delivering a TREM, TREM core fragment or TREM fragment to a cell, tissue, or subject, comprising: providing a cell, tissue, or subject, and contacting the cell, tissue, or subject, a TREM, a TREM core fragment, or a TREM fragment disclosed herein.In an aspect, the disclosure provides a method of modulating a tRNA pool in a cell comprising an endogenous open reading frame (ORE), which ORF comprises a codon having a first sequence, comprising: WO 2024/216206 PCT/US2024/024492 optionally, acquiring knowledge of the abundance of one or both of (i) and (ii), e.g., acquiring knowledge of the relative amounts of: (i) and (ii) in the cell, wherein (i) is a tRNA moiety having an anticodon that pairs with the codon of the ORF having a first sequence (the first tRNA moiety) and (ii) is an isoacceptor tRNA moiety having an anticodon that pairs with a codon other than the codon having the first sequence (the second tRNA moiety) in the cell;contacting the cell with a TREM, a TREM core fragment, or a TREM fragment disclosed herein, wherein the TREM, TREM core fragment or TREM fragment has an anticodon that pairs with: the codon having the first sequence; or the codon other than the codon having the first sequence, in an amount and/or for a time sufficient to modulate the relative amounts of the first tRNA moiety and the second tRNA moiety in the cell,thereby modulating the tRNA pool in the cell.In another aspect, the disclosure provides a method of modulating a tRNA pool in a subject having an ORF, which ORF comprises a codon having a first sequence, comprising: optionally, acquiring knowledge of the abundance of one or both of (i) and (ii), e.g., acquiring knowledge of the relative amounts of: (i) and (ii) in the subject, wherein (i) is a tRNA moiety having an anticodon that pairs with the codon of the ORF having a first sequence (the first tRNA moiety) and (ii) is an isoacceptor tRNA moiety having an anticodon that pairs with a codon other than the codon having the first sequence (the second tRNA moiety) in the subject;contacting the subj ect with a TREM, a TREM core fragment, or a TREM fragment disclosed herein, wherein the TREM, TREM core fragment or TREM fragment has an anticodon that pairs with; the codon having the first sequence; or the codon other than the codon having the first sequence, in an amount and/or for a time sufficient to modulate the relative amounts of the first tRNA moiety and the second tRNA moiety in the subject,thereby modulating the tRNA pool in the subject.In an aspect, the disclosure provides a method of modulating a tRNA pool, e.g., a tRNA pool in a cell or subject having an endogenous ORF, comprising providing a composition comprising a TREM, a TREM core fragment, or a TREM fragment disclosed herein, wherein the TREM, TREM core fragment or TREM fragment comprises a nucleotide sequence modification and/or a non-naturally occurring modification; contacting the subject with the composition in an amount and/or for a time sufficient to modulate the tRNA pool in the subj ect,thereby modulating the tRNA pool in the subject.

WO 2024/216206 PCT/US2024/024492 In an aspect, the disclosure provides a method of modulating expression of a protein in a cell, wherein the protein is encoded by a nucleic acid comprising an ORF, which ORF comprises a codon having a mutation, comprising:contacting the cell with a composition comprising a TREM, a TREM core fragment, or a TREM fragment disclosed herein in an amount and/or for a time sufficient to modulate expression of the encoded protein,wherein the TREM, TREM core fragment or TREM fragment has an anticodon that pairs with the codon having the mutation,thereby modulating expression of the protein in the cell.In another aspect, the disclosure provides a method of modulating expression of a protein in a subject, wherein the protein is encoded by a nucleic acid comprising an endogenous ORF, which ORF comprises a codon having a mutation, comprising:contacting the subject with a composition comprising a TREM, a TREM core fragment, or a TREM fragment disclosed herein, in an amount and/or for a time sufficient to modulate expression of the encoded protein,wherein the TREM, TREM core fragment or TREM fragment has an anticodon that pairs with the codon having the mutation,thereby modulating expression of the protein in the subject.In an embodiment of any of the methods disclosed herein, the mutation in the ORF is a nonsense mutation, e.g., resulting in a premature stop codon chosen from UAA, UGA or UAG. In an embodiment, the stop codon is UAA. In an embodiment, the stop codon is UGA. In an embodiment, the stop codon is UAG.In an embodiment of any of the methods disclosed herein, the TREM comprises an anticodon that pairs with a stop codon.TREMs of the disclosure include TREMs, TREM core fragments and TREM fragments. TREMs, TREM core fragments or TREM fragments can be modified with non-naturally occurring modifications to, e.g., increase the level and/or activity (e.g., stability) of the TREM. Pharmaceutical TREM compositions, e.g., comprising TREMs having a non-naturally occurring modification, can be administered to cells, tissues or subjects to modulate these functions, e.g., in vitro or in vivo. Disclosed herein are TREMs, TREM core fragments or TREM fragments WO 2024/216206 PCT/US2024/024492 comprising non-naturally occurring modifications, TREM compositions, preparations, methods of making TREM compositions and preparations, and methods of using the same.In an embodiment, the TREM, TREM core fragment, and TREM fragments comprise a non-naturally occurring modification that improves stability or enhances activity of the TREM, TREM core fragment, or TREM fragment.Additional features of any of the aforesaid TREMs, TREM core fragments, TREM fragments, TREM compositions, preparations, methods of making TREM compositions and preparations, and methods of using TREM compositions and preparations include one or more of the features in the Enumerated Embodiments, Figures, Description, Examples, or Claims.Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following Enumerated Embodiments, Drawings, Description, Examples, or Claims.

BRIEF DESCRIPTION OF DRAWINGS FIGs. 1-2are graphs showing activity of TREMs for read-though of a premature termination codon (PTC) engineered in a NanoLuc reporter protein to produce a functional NanoLuc protein in a cell line stably expressing the NanoLuc reporter protein upon transduction with TREM expression constructs. FIG. lisa graph comparing the 10g2 PTC read-though activity of TREMs consisting of the nucleotide sequence scaffolds listed in Table 7 modified with each of the chemical modification patterns listed in Table 6. FIG. 2is a graph comparing the log2 PTC readthrough activity of TREMs consisting of the nucleotide sequence scaffolds listed in Table 7 comprising 0 to 41 chemically modified nucleotides. FIG. 3is a table listing exemplary TREMs described herein. FIG. 4shows the abundance of nucleotide substitutions at each position of various TREM scaffolds in a pool of hits resulting from a pooled screen for PTC read-through activity of TREMs comprising nucleotide substitutions. The SEQ ID NOs indicate reference TREMs from which the pool of TREMs having nucleotide substitutions is generated for screening. FIG. 4Ais a schematic representation of a TREM indicating regions where nucleotide substitutions typically result in increased PTC read-through activity, e.g., typically positive, typically result in decreased PTC read-through activity, e.g., typically negative, or result in increased PTC read- WO 2024/216206 PCT/US2024/024492 through activity for certain scaffolds, e.g., scaffold-specific positive. FIG. 4Bshows the normalized hit abundance for nucleotide substitutions at each position in various TREM scaffolds, e.g., the frequency at which each position within a TREM comprises a nucleotide substitution in the pool of hits from a screen for increased PTC read-through activity. FIG. 5is a heatmap showing the enrichment of nucleotide substitutions, e.g., mutated sites, at each position of various TREM scaffolds in a pool of hits resulting from a pooled screen for PTC read-through activity of TREMs comprising nucleotide substitutions, e.g., showing the frequency at which each position within a TREM comprises a nucleotide substitution in the pool of hits from a screen for increased PTC read-through activity. The SEQ IDNOs indicate reference TREMs from which the pool of TREMs comprising nucleotide substitutions is generated for screening. The boxed regions indicate positions where nucleotide substitutions result in increased activity of a TREM. FIGs. 6-15are graphs showing the abundance of nucleotide substitutions at each position of various TREM scaffolds in a pool of hits resulting from a pooled screen for PTC read-through activity of TREMs comprising nucleotide substitutions. The SEQ ID NOs indicate reference TREMs from which the pool of TREMs comprising nucleotide substitutions is generated for screening. FIG. 6shows the normalized hit abundance for nucleotide substitutions at each position in an Arg-TGA reference scaffold (SEQ ID NO: 1638). FIG.7 shows the normalized hit abundance for nucleotide substitutions at each position in a Gln-TAG reference scaffold (SEQ ID NO: 1835). FIG. 8shows the normalized hit abundance for nucleotide substitutions at each position in two Gln-TAG reference scaffolds (SEQ ID NOs: 1660 and 1654) resulting from the first round of pooled screening shown in FIG. 7. FIG. 9shows the aggregate normalized hit abundance for nucleotide substitutions at each position in three Glu-TAG reference scaffolds (SEQ ID NOs: 1867, 2000, and 2001). FIG. 10shows the normalized hit abundance for nucleotide substitutions at each position in a Glu-TAG reference scaffold (SEQ ID NO: 1867). FIG. 11shows the normalized hit abundance for nucleotide substitutions at each position in a Glu-TAG reference scaffold (SEQ ID NO: 2000). FIG. 12shows the normalized hit abundance for nucleotide substitutions at each position in two Leu-TAG reference scaffolds (SEQ ID NOs: 2016 and 2017). FIG. 13shows the normalized hit abundance for nucleotide substitutions at each position in two Tyr-TAG reference scaffolds (SEQ ID NOs: 2022 and 2023). FIG. 14 shows the normalized hit abundance for nucleotide substitutions at each position in two Ser-TAG WO 2024/216206 PCT/US2024/024492 reference scaffolds (SEQ ID NOs: 2020 and 2021). FIG. 15shows the normalized hit abundance for nucleotide substitutions at each position in two Lys-TAG reference scaffolds (SEQ ID NOs: 2018 and 2019). FIG. 16is a heatmap showing enrichment for disrupted base-pairing at each position of various TREM scaffolds resulting from a pooled screen for PTC read-through activity of TREMs having nucleotide substitutions. The SEQ ID NOs indicate reference TREMs from which the pool of TREMs comprising nucleotide substitutions is generated for screening. The boxed regions indicate positions where nucleotide substitutions that disrupt base pairing result in increased activity of a TREM. FIG. 17 is a scatter plot showing the enrichment score for TREMs in a Gln-TAG pooled screen. Candidates are colored in gray, negative control TREMs in black, and human-based tRNAs with anticodons cognate to the TAG PTC in as positive controls magenta. The hit threshold is indicated as vertical and horizontal dashed lines, with candidates in the upper right quadrant designated as hits. FIG. 18 is a graph showing a luciferase reporter assay performed on candidates shown in FIG. 17 selected for hit validation. The starting sequence from which variants were then created is shown in magenta, and the activity of all tested sequences was evaluated at two concentrations. FIGs. 19A-Bshow the enrichment score for TREMs in a Glu-TAG pooled screen. FIG. 19Ashows candidate TREMs are colored in light gray, negative control TREMs in dark gray, and human-based tRNAs with anticodons cognate to the TAG PTC as positive controls in magenta. The hit threshold is indicated as vertical and horizontal dashed lines, with candidates in the upper right quadrant designated as hits. FIG. 19Bshows Glu-TAG TREM hits resulting from the screen. FIGs. 20A-Bshow a luciferase reporter assay performed on candidates shown in FIG. selected for hit validation. FIGs. 21A-Cshow schematics of TREMs from hits shown in FIG. 20. FIG. 21Ashows the parent TREM. FIG. 21Bshows a Glu-TAG TREM hit. FIG. 21Cshows a Glu-TAG TREM hit.

WO 2024/216206 PCT/US2024/024492 FIG. 22 is a scatter plot showing the results of a luciferase reporter assay performed on candidate TREMs selected for hit validation as both synthesized oligonucleotides and as lentiviral particles. The parent sequence is shown in magenta, with hits shown in gray. FIG. 23 is a table listing exemplary TREMs described herein. FIG. 24 is a table listing the effect of nucleotide substitutions on the PTC read-through activity of TREMs listed in FIG. 23. "Sub. " indicates substitution; "compens. " indicates compensatory; "rel. " indicates relative. FIG. 25 is a table comparing the PTC read-through activity of hits from a pooled screen of TREMs comprising nucleotide substitutions measured by validation as synthesized oligonucleotides or by lentiviral delivery.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS The present disclosure features tRNA-based effector molecules (TREMs), compositions, and related methods useful for optimizing a functional parameter of the TREM, for example, by introducing a nucleotide sequence modification, a non-naturally occurring chemical modification, or both into the TREM sequence. As disclosed herein, TREMs are complex molecules which can mediate a variety of cellular processes. The inventors have discovered that the nucleotide sequence of a TREM can be optimized to modulate a functional parameter of a TREM; the methods described herein describe how a plurality of sequences (e.g., tens, hundreds, or thousands) may be screened in order to select for a TREM sequence bearing a different functional readout. For example, out of a pooled screen of TREM sequences in which each nucleotide position of the TREM has been substituted with another nucleotide sequence, TREM sequences may be analyzed to select those TREMs that contain certain nucleotide substitutions that may, e.g., enhance the TREM for a certain function, such as improved readthrough of a premature termination codon (PTC), in a transcript.Pharmaceutical TREM compositions, e.g., the TREMs described herein, can be administered to a cell, a tissue, or to a subject to modulate certain cellular functions. Also disclosed herein are methods of modulating expression of a protein in a subject or cell, wherein the protein is encoded by a nucleic acid comprising an endogenous open reading frame (ORF) having a first sequence, e.g., a mutation, e.g., a premature termination codon (PTC), and methods of treating a subject having an endogenous open reading frame (ORF) which comprises a WO 2024/216206 PCT/US2024/024492 premature termination codon (PTC). Further disclosed herein are TREMs comprising a non- naturally occurring modification, methods of making the same and compositions thereof.

Definitions"Acquire " or "acquiring " as the terms are used herein, refer to obtaining possession of a value, e.g, a numerical value, by "directly acquiring " or "indirectly acquiring " the physical entity or value. "Directly acquiring " refers to performing a process (e.g., performing an analytical method) to obtain the value. "Indirectly acquiring " refers to receiving the value from another party or source (e.g., a third party laboratory that directly acquired the or value).A "disease or disorder associated with a PTC" as that term is used herein includes, but is not limited to, a disease or disorder in which cells express, or at one time expressed, a polypeptide encoded by an ORF comprising a PTC. In some embodiments, a disease associated with a PTC is chosen from: a proliferative disorder (e.g., a cancer), a genetic disorder, a metabolic disorder, an immune disorder, an inflammatory disorder or a neurological disorder. Exemplary diseases or disorders associated with a PTC are provided in any one of Tables 15, and 17. In an embodiment, the disease associated with a PTC is a cancer. In an embodiment, the disease associated with a PTC is a monogenic disease.An "isoacceptor, " as that term is used herein, refers to a plurality of tRNA molecule or TREMs wherein each molecule of the plurality comprises a different naturally occurring anticodon sequence and each molecule of the plurality mediates the incorporation of the same amino acid and that amino acid is the amino acid that naturally corresponds to the anticodons of the plurality.A "modification, " as that term is used herein in regard to a TREM, may refer to a sequence modification or a chemical modification of the TREM. As this term is used to in reference to a sequence modification, the modification may include a nucleotide addition, nucleotide deletion or nucleotide substitution. As this term is used in reference to a chemical modification, the modification may include a modification of the chemical structure, e.g., a covalent modification, of the subject nucleotide. The chemical modification can be naturally occurring or non-naturally occurring. In an embodiment, the modification is non-naturally occurring. In an embodiment, the modification is naturally occurring. In an embodiment, the WO 2024/216206 PCT/US2024/024492 modification is a synthetic modification. In an embodiment, the modification is a modification provided in Table 5.A "naturally occurring nucleotide, " as that term is used herein, refers to a nucleotide that does not comprise a non-naturally occurring modification. In an embodiment, it includes a naturally occurring modification.A "non-naturally occurring modification, " as that term is used herein with reference to a nucleotide, refers to a chemical modification that: (a) a cell, e.g., a human cell, does not make on an endogenous tRNA; or (b) a cell, e.g., a human cell, can make on an endogenous tRNA but wherein such modification is in a location in which it does not occur on a native tRNA, e.g., the modification is in a domain, linker or arm, or on a nucleotide and/or at a position within a domain, linker or arm, which does not have such modification in nature. In either case, the modification is added synthetically, e.g., in a cell free reaction, e.g., in a solid state or liquid phase synthetic reaction. In an embodiment, the non-naturally occurring modification is a modification that is not present (in identity, location or position) if a sequence of the TREM is expressed in a mammalian cell, e.g., a HEK293 cell line. Exemplary non-naturally occurring modifications are found in Table 5.A "non-naturally modified nucleotide, " as that term is used herein, refers a nucleotide comprising a non-naturally occurring modification on or of a sugar, nucleobase, or phosphate moiety.A "nucleotide, " as that term is used herein, refers to an entity comprising a sugar, typically a pentameric sugar; a nucleobase; and a phosphate linking group. In an embodiment, a nucleotide comprises a naturally occurring, e.g., naturally occurring in a human cell, nucleotide, e.g., an adenine, thymine, guanine, cytosine, or uracil nucleotide.A "premature termination codon " or "PTC" as those terms are used herein, refer to a stop codon that occurs in an open reading frame (ORF) of a DNA or mRNA. In an embodiment, a PTC occurs at a position upstream of a naturally occurring stop codon in an ORF. In an embodiment, a PTC that occurs upstream of a naturally occurring stop codon, e.g., in an ORF, results in modulation of a production parameter of the corresponding mRNA or polypeptide encoded by the ORF. In an embodiment, a PTC can differ (or arise) from a pre-mutation sequence by a point mutation, e.g., a nonsense mutation. In an embodiment, a PTC can differ (or arise) from a pre-mutation sequence by a genetic change, e.g., abnormality, other than a point WO 2024/216206 PCT/US2024/024492 mutation, e.g., a frameshift, a deletion, an insertion, a rearrangement, an inversion, a translocation, a duplication, or a transversion. In an embodiment, a PTC results in the production of a truncated protein which lacks a native activity or which is associated with a mutant, disease, or other unwanted phenotype. In an embodiment, the ORF comprising the PTC is an ORF from a tumor suppressor gene. In an embodiment, the mutation giving rise to the PTC is a driver mutation, e.g., a mutation that provides a growth advantage to a tumor cell.A "functional parameter, " refers to an expression parameter and/or a signaling parameter. In an embodiment a functional parameter is an expression parameter. An expression parameter includes an expression parameter of a polypeptide or protein encoded by the endogenous ORF having a first sequence or PTC; or an expression parameter of an RNA, e.g., messenger RNA, encoded by the endogenous ORF having a first sequence or PTC. In an embodiment, an expression parameter can include:(a) protein translation;(b) expression level (e.g., of polypeptide or protein, or mRNA);(c) post-translational modification of polypeptide or protein;(d) folding (e.g., of polypeptide or protein, or mRNA),(e) structure (e.g., of polypeptide or protein, or mRNA),(f) transduction (e.g., of polypeptide or protein),(g) compartmentalization (e.g., of polypeptide or protein, or mRNA),(h) incorporation (e.g., of polypeptide or protein, or mRNA) into a supermolecular structure, e.g., incorporation into a membrane, proteasome, or ribosome,(i) incorporation into a multimeric polypeptide, e.g., a homo or heterodimer, and/or(j) stability.In an embodiment, a functional parameter is a signaling parameter. A signaling parameter can include:(1) modulation of a signaling pathway, e.g., a cellular signaling pathway which is downstream or upstream of the protein encoded by the endogenous ORF having a first sequence or PTC;(2) cell fate modulation;(3) ribosome occupancy modulation;(4) protein translation modulation; WO 2024/216206 PCT/US2024/024492 (5) mRNA stability modulation;(6) protein folding and structure modulation;(7) protein transduction or compartmentalization modulation; and/or(8) protein stability modulation.An "ORF having a PTC" as that phrase is used herein, refers to an open reading frame (ORF) which comprises a premature termination codon (PTC). In an embodiment, the ORF having the PTC is associated with a disease or disorder associated with a PTC, e.g., as described herein, e.g., a disease or disorder listed in any one of Tables 15, 16 and 17. In an embodiment, the ORF having the PTC is not associated with a disease or disorder associated with a PTC.A "stop codon " as that term is used herein, refers to a three nucleotide contiguous sequence within messenger RNA that specifies a termination of translation. For example, UAG, UAA, UGA (in RNA) and TAG, TAA or TGA (in DNA) are stop codons. The stop codons are also known as amber (UAG), ochre (UAA), and opal (UGA).A "tRNA-based effector molecule " or "TREM," as that term is used herein, refers to an RNA molecule comprising a structure or property from (a)-(v) below, and which is a recombinant TREM, a synthetic TREM, or a TREM expressed from a heterologous cell. The TREMs described in the present invention are synthetic molecules and are made, e.g., in a cell free reaction, e.g., in a solid state or liquid phase synthetic reaction. TREMs are chemically distinct, e.g., in terms of primary sequence, type or location of modifications from the endogenous tRNA molecules made in cells, e.g., in mammalian cells, e.g., in human cells. A TREM can have a plurality (e.g., 2, 3, 4, 5, 6, 7, 8, 9) of the structures and functions of (a)-(v).In an embodiment, a TREM is non-native, as evaluated by structure or the way in which it was made.In an embodiment, a TREM comprises one or more of the following structures or properties:(a ’) an optional linker region of a consensus sequence provided in the "Consensus Sequence " section, e.g., a Linker 1 region;(a) an amino acid attachment domain that binds an amino acid, e.g., an acceptor stem domain (AStD), wherein an AStD comprises sufficient RNA sequence to mediate, e.g., when present in an otherwise wildtype tRNA, acceptance of an amino acid, e.g., its cognate amino acid or a non-cognate amino acid, and transfer of the amino acid (AA) in the initiation or elongation WO 2024/216206 PCT/US2024/024492 of a polypeptide chain. Typically, the AStD comprises a 3’-end adenosine (CCA) for acceptor stem charging which is part of synthetase recognition. In an embodiment the AStD has at least 75, 80, 85, 85, 90, 95, or 100% identity with a naturally occurring AStD, e.g., an AStD encoded by a nucleic acid in Table 1. In an embodiment, the TREM can comprise a fragment or analog of an AStD, e.g., an AStD encoded by a nucleic acid in Table 1, which fragment in embodiments has AStD activity and in other embodiments does not have AStD activity. (One of ordinary skill can determine the relevant corresponding sequence for any of the domains, stems, loops, or other sequence features mentioned herein from a sequence encoded by a nucleic acid in Table 1. E.g., one of ordinary skill can determine the sequence which corresponds to an AStD from a tRNA sequence encoded by a nucleic acid in Table 1.)In an embodiment the AStD falls under the corresponding sequence of a consensus sequence provided in the "Consensus Sequence " section, or differs from the consensus sequence by no more than 1, 2, 5, or 10 positions;In an embodiment, the AStD comprises residues R1-R2-R3-R4 -R5-R6-R7and residues R6s- R66-R67-R6s-R69-R70-R71 of Formula 1 zzz, wherein ZZZ indicates any of the twenty amino acids;In an embodiment, the AStD comprises residues R-R2-R3-R4 -R5-R6-R7and residues R65- R66-R67-R6s-R69-R7o-R71 of Formula II zzz, wherein ZZZ indicates any of the twenty amino acids;In an embodiment, the AStD comprises residues R1-R2-R3-R4 -R5-R6-R7and residues R6s- R66-R67-R6s-R69-R70-R71 of Formula III zzz, wherein ZZZ indicates any of the twenty amino acids;(a ’-l) a linker comprising residues R8-R9 of a consensus sequence provided in the "Consensus Sequence " section, e.g., a Linker 2 region;(b) a dihydrouridine hairpin domain (DHD), wherein a DHD comprises sufficient RNA sequence to mediate, e.g., when present in an otherwise wildtype tRNA, recognition of aminoacyl-tRNA synthetase, e.g, acts as a recognition site for aminoacyl-tRNA synthetase for amino acid charging of the TREM. In embodiments, a DHD mediates the stabilization of the TREM’s tertiary structure. In an embodiment the DHD has at least 75, 80, 85, 85, 90, 95, or 100% identity with a naturally occurring DHD, e.g, a DHD encoded by a nucleic acid in Table 1. In an embodiment, the TREM can comprise a fragment or analog of a DHD, e.g., a DHD encoded by a nucleic acid in Table 1, which fragment in embodiments has DHD activity and in other embodiments does not have DHD activity.

WO 2024/216206 PCT/US2024/024492 In an embodiment the DHD falls under the corresponding sequence of a consensus sequence provided in the "Consensus Sequence " section, or differs from the consensus sequence by no more than 1, 2, 5, or 10 positions;In an embodiment, the DHD comprises residues R1-R11-R12-R13-R14 R15-R16-R17-R18- R19-R20-R21-R22-R23-R24-R25-R26-R27-R28 of Formula 1 zzz, wherein ZZZ indicates any of the twenty amino acids;In an embodiment, the DHD comprises residues R10-R11-R12-R13-R14 R15-R16-R17-R18- R19-R20-R21-R22-R23-R24-R25-R26-R27-R28 of Formula II zzz, wherein ZZZ indicates any of the twenty amino acids;In an embodiment, the DHD comprises residues R10-R11-R12-R13-R14 R15-R16-R17-R18- R19-R20-R21-R22-R23-R24-R25-R26-R27-R28 of Formula III zzz, wherein ZZZ indicates any of the twenty amino acids;(b’-l) a linker comprising residue R29 of a consensus sequence provided in the "Consensus Sequence " section, e.g., a Linker 3 region;(c) an anticodon that binds a respective codon in an mRNA, e.g., an anticodon hairpin domain (ACHD), wherein an ACHD comprises sufficient sequence, e.g., an anticodon triplet, to mediate, e.g., when present in an otherwise wildtype tRNA, pairing (with or without wobble) with a codon; In an embodiment the ACHD has at least 75, 80, 85, 85, 90, 95, or 100% identity with a naturally occurring ACHD, e.g., an ACHD encoded by a nucleic acid in Table 1. In an embodiment, the TREM can comprise a fragment or analog of an ACHD, e.g., an ACHD encoded by a nucleic acid in Table 1, which fragment in embodiments has ACHD activity and in other embodiments does not have ACHD activity.In an embodiment the ACHD falls under the corresponding sequence of a consensus sequence provided in the "Consensus Sequence " section, or differs from the consensus sequence by no more than 1, 2, 5, or 10 positions;In an embodiment, the ACHD comprises residues -R30-R31-R32-R33-R34-R35-R36-R37-R38- R39-R40-R41-R42-R43-R44-R45-R46 of Formula 1 zzz, wherein ZZZ indicates any of the twenty amino acids;In an embodiment, the ACHD comprises residues -R30-R31-R32-R33-R34-R35-R36-R37-R38- R39-R40-R41-R42-R43-R44-R45-R46 of Formula II zzz, wherein ZZZ indicates any of the twenty amino acids; WO 2024/216206 PCT/US2024/024492 In an embodiment, the ACHD comprises residues -R30-R31-R32-R33-R34-R35-R36-R37-R38- R39-R40-R41-R42-R43-R44-R45-R46 of Formula III zzz, wherein ZZZ indicates any of the twenty amino acids;(d) a variable loop domain (VLD), wherein a VLD comprises sufficient RNA sequence to mediate, e.g., when present in an otherwise wildtype tRNA, recognition of aminoacyl-tRNA synthetase, e.g., acts as a recognition site for aminoacyl-tRNA synthetase for amino acid charging of the TREM. In embodiments, a VLD mediates the stabilization of the TREM’s tertiary structure. In an embodiment, a VLD modulates, e.g., increases, the specificity of the TREM, e.g., for its cognate amino acid, e.g., the VLD modulates the TREM’s cognate adaptor function. In an embodiment the VLD has at least 75, 80, 85, 85, 90, 95, or 100% identity with a naturally occurring VLD, e.g., a VLD encoded by a nucleic acid in Table 1. In an embodiment, the TREM can comprise a fragment or analog of a VLD, e.g., a VLD encoded by a nucleic acid in Table 1, which fragment in embodiments has VLD activity and in other embodiments does not have VLD activity.In an embodiment the VLD falls under the corresponding sequence of a consensus sequence provided in the "Consensus Sequence " section.In an embodiment, the VLD comprises residue -[R47]x0f a consensus sequence provided in the "Consensus Sequence " section, wherein x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l- 175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l21 ־, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-l l, x=l-10, x=10-271, x=20-271, x=30-271, x=40-271, x=50-271, x=60-271, x=70-271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=l l, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271);(e) a thymine hairpin domain (THD), wherein a THD comprises sufficient RNA sequence, to mediate, e.g., when present in an otherwise wildtype tRNA, recognition of the ribosome, e.g., acts as a recognition site for the ribosome to form a TREM-ribosome complex during translation. In an embodiment the THD has at least 75, 80, 85, 85, 90, 95, or 100% identity with a naturally occurring THD, e.g., a THD encoded by a nucleic acid in Table 1. In an WO 2024/216206 PCT/US2024/024492 embodiment, the TREM can comprise a fragment or analog of a THD, e.g., a THD encoded by a nucleic acid in Table 1, which fragment in embodiments has THD activity and in other embodiments does not have THD activity.In an embodiment the THD falls under the corresponding sequence of a consensus sequence provided in the "Consensus Sequence " section, or differs from the consensus sequence by no more than 1, 2, 5, or 10 positions;In an embodiment, the THD comprises residues -R4s-R49-R50-R51-R52-R53-R54-R55-R56- R57-R58-R59-R60-R61-R62-R63-R64 of Formula 1 zzz, wherein ZZZ indicates any of the twenty amino acids;In an embodiment, the THD comprises residues -R4s-R49-R50-R51-R52-R53-R54-R55-R56- R57-R58-R59-R60-R61-R62-R63-R64 of Formula 11 zzz, wherein ZZZ indicates any of the twenty amino acids;In an embodiment, the THD comprises residues -R4s-R49-R50-Rs1-R52-R53-R54-R55-R56- R57-R58-R59-R60-R61-R62-R63-R64 of Formula III zzz, wherein ZZZ indicates any of the twenty amino acids;(e ’ l) a linker comprising residue R72 of a consensus sequence provided in the "Consensus Sequence " section, e.g., a Linker 4 region;(f) under physiological conditions, it comprises a stem structure and one or a plurality of loop structures, e.g., 1, 2, or 3 loops. A loop can comprise a domain described herein, e.g., a domain selected from (a)-(e). A loop can comprise one or a plurality of domains. In an embodiment, a stem or loop structure has at least 75, 80, 85, 85, 90, 95, or 100% identity with a naturally occurring stem or loop structure, e.g., a stem or loop structure encoded by a nucleic acid in Table 1. In an embodiment, the TREM can comprise a fragment or analog of a stem or loop structure, e.g., a stem or loop structure encoded by a nucleic acid in Table 1, which fragment in embodiments has activity of a stem or loop structure, and in other embodiments does not have activity of a stem or loop structure;(g) a tertiary structure, e.g., an L-shaped tertiary structure;(h) adaptor function, i.e., the TREM mediates acceptance of an amino acid, e.g., its cognate amino acid and transfer of the AA in the initiation or elongation of a polypeptide chain; WO 2024/216206 PCT/US2024/024492 (i) cognate adaptor function wherein the TREM mediates acceptance and incorporation of an amino acid (e.g., cognate amino acid) associated in nature with the anti-codon of the TREM to initiate or elongate a polypeptide chain;(j) non-cognate adaptor function, wherein the TREM mediates acceptance and incorporation of an amino acid (e.g, non-cognate amino acid) other than the amino acid associated in nature with the anti-codon of the TREM in the initiation or elongation of a polypeptide chain;(k) a regulatory function, e.g., an epigenetic function (e.g., gene silencing function or signaling pathway modulation function), cell fate modulation function, mRNA stability modulation function, protein stability modulation function, protein transduction modulation function, or protein compartmentalization function;(1) a structure which allows for ribosome binding;(m) a post-transcriptional modification, e.g., a naturally occurring post-trasncriptional modification;(n) the ability to inhibit a functional property of a tRNA, e.g., any of properties (h)-(k) possessed by a tRNA;(o) the ability to modulate cell fate;(p) the ability to modulate ribosome occupancy;(q) the ability to modulate protein translation;(r) the ability to modulate mRNA stability;(s) the ability to modulate protein folding and structure;(t) the ability to modulate protein transduction or compartmentalization;(u) the ability to modulate protein stability; or(v) the ability to modulate a signaling pathway, e.g., a cellular signaling pathway.In an embodiment, a TREM comprises a full-length tRNA molecule or a fragment thereof.In an embodiment, a TREM comprises the following properties; (a)-(e).In an embodiment, a TREM comprises the following properties: (a) and (c).In an embodiment, a TREM comprises the following properties: (a), (c) and (h).In an embodiment, a TREM comprises the following properties: (a), (c), (h) and (b).In an embodiment, a TREM comprises the following properties: (a), (c), (h) and (e).

WO 2024/216206 PCT/US2024/024492 In an embodiment, a TREM comprises the following properties: (a), (c), (h), (b) and (e).In an embodiment, a TREM comprises the following properties: (a), (c), (h), (b), (e) and (g).In an embodiment, a TREM comprises the following properties: (a), (c), (h) and (m).In an embodiment, a TREM comprises the following properties: (a), (c), (h), (m), and (g). In an embodiment, a TREM comprises the following properties: (a), (c), (h), (m) and (b). In an embodiment, a TREM comprises the following properties: (a), (c), (h), (m) and (e). In an embodiment, a TREM comprises the following properties: (a), (c), (h), (m), (g), (b) and (e).In an embodiment, a TREM comprises the following properties: (a), (c), (h), (m), (g), (b), (e) and (q).In an embodiment, a TREM comprises:(i) an amino acid attachment domain that binds an amino acid (e.g., an AStD, as described in (a) herein; and(ii) an anticodon that binds a respective codon in an mRNA (e-g•, an ACHD, as described in (c) herein).In an embodiment the TREM comprises a flexible RNA linker which provides for covalent linkage of (i) to (ii).In an embodiment, the TREM mediates protein translation.In an embodiment a TREM comprises a linker, e.g., an RNA linker, e.g., a flexible RNA linker, which provides for covalent linkage between a first and a second structure or domain. In an embodiment, an RNA linker comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or ribonucleotides. A TREM can comprise one or a plurality of linkers, e.g., in embodiments a TREM comprising (a), (b), (c), (d) and (e) can have a first linker between a first and second domain, and a second linker between a third domain and another domain.In an embodiment, the TREM comprises a sequence of Formula A: [Ll]-[ASt Domainl]- [L2]-[DH Domain]-[L3]-[ACH Domain] -[VL Domain]-[TH Domain]-[L4]-[ASt Domain2].In an embodiment, a TREM comprises an RNA sequence at least 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical with, or which differs by no more than 1, 2, 3, 4, 5, 10, 15, 20, 25, or 30 ribonucleotides from, an RNA sequence encoded by a DNA sequence listed in Table 1, or a fragment or functional fragment thereof. In an embodiment, a TREM comprises an WO 2024/216206 PCT/US2024/024492 RNA sequence encoded by a DNA sequence listed in Table 1, or a fragment or functional fragment thereof. In an embodiment, a TREM comprises an RNA sequence encoded by a DNA sequence at least 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical with a DNA sequence listed in Table 1, or a fragment or functional fragment thereof. In an embodiment, a TREM comprises a TREM domain, e.g., a domain described herein, comprising at least 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, or 99% identical with, or which differs by no more than 1, 2, 3, 4, 5, 10, or 15, ribonucleotides from, an RNA encoded by a DNA sequence listed in Table 1, or a fragment or a functional fragment thereof. In an embodiment, a TREM comprises a TREM domain, e.g., a domain described herein, comprising an RNA sequence encoded by DNA sequence listed in Table 1, or a fragment or functional fragment thereof. In an embodiment, a TREM comprises a TREM domain, e.g., a domain described herein, comprising an RNA sequence encoded by DNA sequence at least 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98 or 99% identical with a DNA sequence listed in Table 1, or a fragment or functional fragment thereof.In an embodiment, a TREM is 76-90 nucleotides in length. In embodiments, a TREM or a fragment or functional fragment thereof is between 10-90 nucleotides, between 10-nucleotides, between 10-70 nucleotides, between 10-60 nucleotides, between 10-50 nucleotides, between 10-40 nucleotides, between 10-30 nucleotides, between 10-20 nucleotides, between 20- nucleotides, between 20-80 nucleotides, 20-70 nucleotides, between 20-60 nucleotides, between 20-50 nucleotides, between 20-40 nucleotides, between 30-90 nucleotides, between 30- nucleotides, between 30-70 nucleotides, between 30-60 nucleotides, or between 30-nucleotides.In an embodiment, a TREM is aminoacylated, e.g., charged, with an amino acid by an aminoacyl tRNA synthetase.In an embodiment, a TREM is not charged with an amino acid, e.g., an uncharged TREM (uTREM).In an embodiment, a TREM comprises less than a full length tRNA. In embodiments, a TREM can correspond to a naturally occurring fragment of a tRNA, or to a non-naturally occurring fragment. Exemplary fragments include: TREM halves (e.g., from a cleavage in the ACHD, e.g., in the anticodon sequence, e.g., 5’halves or 3’ halves); a 5’ fragment (e.g., a fragment comprising the 5’ end, e.g., from a cleavage in a DHD or the ACHD); a 3’ fragment WO 2024/216206 PCT/US2024/024492 (e.g, a fragment comprising the 3’ end, e.g., from a cleavage in the THD); or an internal fragment (e.g., from a cleavage in one or more of the ACHD, DHD or THD).A "TREM core fragment, " as that term is used herein, refers to a portion of the sequence of Formula B: [El] y -[ASt Domainl] X-[L2] y -[DH Domain] y -[L3] y -[ACH Domain] x -[VL Domain] y -[TH Domain] y -[L4] y -[ASt Domain2] x , wherein: x=l and y=0 or 1.A "TREM fragment, " as used herein, refers to a portion of a TREM, wherein the TREM comprises a sequence of Formula A: [Ll]-[ASt Domainl]-[L2]-[DH Domain]-[L3]-[ACH Domain] -[VL Domain]-[TH Domain]-[L4]-[ASt Domain2].A "cognate adaptor function TREM," as that term is used herein, refers to a TREM which mediates initiation or elongation with the AA (the cognate AA) associated in nature with the anti-codon of the TREM."Decreased expression, " as that term is used herein, refers to a decrease in comparison to a reference, e.g., in the case where altered control region, or addition of an agent, results in a decreased expression of the subject product, it is decreased relative to an otherwise similar cell without the alteration or addition.An "exogenous nucleic acid, " as that term is used herein, refers to a nucleic acid sequence that is not present in or differs by at least one nucleotide from the closest sequence in a reference cell, e.g., a cell into which the exogenous nucleic acid is introduced. In an embodiment, an exogenous nucleic acid comprises a nucleic acid that encodes a TREM.An "exogenous TREM," as that term is used herein, refers to a TREM that:(a) differs by at least one nucleotide or one post transcriptional modification from the closest sequence tRNA in a reference cell, e.g., a cell into which the exogenous nucleic acid is introduced;(b) has been introduced into a cell other than the cell in which it was transcribed;(c) is present in a cell other than one in which it naturally occurs; or(d) has an expression profile, e.g., level or distribution, that is non-wildtype, e.g., it is expressed at a higher level than wildtype. In an embodiment, the expression profile can be mediated by a change introduced into a nucleic acid that modulates expression or by addition of an agent that modulates expression of the RNA molecule. In an embodiment an exogenous TREM comprises 1, 2, 3 or 4 of properties (a)-(d).

WO 2024/216206 PCT/US2024/024492 A "GMP-grade composition, " as that term is used herein, refers to a composition in compliance with current good manufacturing practice (cGMP) guidelines, or other similar requirements. In an embodiment, a GMP-grade composition can be used as a pharmaceutical product.As used herein, the terms "increasing " and "decreasing " refer to modulating that results in, respectively, greater or lesser amounts of function, expression, or activity of a particular metric relative to a reference. For example, subsequent to administration to a cell, tissue or subject of a TREM described herein, the amount of a marker of a metric (e.g., protein translation, mRNA stability, protein folding) as described herein may be increased or decreased by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 98%, 2X, 3X, 5X, 10X or more relative to the amount of the marker prior to administration or relative to the effect of a negative control agent. The metric may be measured subsequent to administration at a time that the administration has had the recited effect, e.g., at least 12 hours, 24 hours, one week, one month, 3 months, or 6 months, after a treatment has begun."Increased expression, " as that term is used herein, refers to an increase in comparison to a reference, e.g., in the case where altered control region, or addition of an agent, results in an increased expression of the subject product, it is increased relative to an otherwise similar cell without the alteration or addition.A "non-cognate adaptor function TREM," as that term is used herein, refers to a TREM which mediates initiation or elongation with an AA (a non-cognate AA) other than the AA associated in nature with the anti-codon of the TREM. In an embodiment, a non-cognate adaptor function TREM is also referred to as a mischarged TREM (mTREM).A "non-naturally occurring sequence, " as that term is used herein, refers to a sequence wherein an Adenine is replaced by a residue other than an analog of Adenine, a Cytosine is replaced by a residue other than an analog of Cytosine, a Guanine is replaced by a residue other than an analog of Guanine, and a Uracil is replaced by a residue other than an analog of Uracil. An analog refers to any possible derivative of the ribonucleotides, A, G, C or U. In an embodiment, a sequence having a derivative of any one of ribonucleotides A, G, C or U is a non- naturally occurring sequence.

WO 2024/216206 PCT/US2024/024492 A "pharmaceutical TREM composition, " as that term is used herein, refers to a TREM composition that is suitable for pharmaceutical use. Typically, a pharmaceutical TREM composition comprises a pharmaceutical excipient. In an embodiment the TREM will be the only active ingredient in the pharmaceutical TREM composition. In embodiments the pharmaceutical TREM composition is free, substantially free, or has less than a pharmaceutically acceptable amount, of host cell proteins, DNA, e.g, host cell DNA, endotoxins, and bacteria.A "post-transcriptional processing, " as that term is used herein, with respect to a subject molecule, e.g., a TREM, RNA or tRNAs, refers to a covalent modification of the subject molecule. In an embodiment, the covalent modification occurs post-transcriptionally. In an embodiment, the covalent modification occurs co-transcriptionally. In an embodiment the modification is made in vivo, e.g., in a cell used to produce a TREM. In an embodiment the modification is made ex vivo, e.g., it is made on a TREM isolated or obtained from the cell which produced the TREM. In an embodiment, the post-transcriptional modification is selected from a post-transcriptional modification listed in Table 2.A "tRNA ", as that term is used herein, refers to a naturally occurring transfer ribonucleic acid in its native state.A "TREM composition, " as that term is used herein, refers to a composition comprising a plurality of TREMs, a plurality of TREM core fragments and/or a plurality of TREM fragments. A TREM composition can comprise one or more species of TREMs, TREM core fragments or TREM fragments. In an embodiment, the composition comprises only a single species of TREM, TREM core fragment or TREM fragment. In an embodiment, the TREM composition comprises a first TREM, TREM core fragment or TREM fragment species; and a second TREM, TREM core fragment or TREM fragment species. In an embodiment, the TREM composition comprises X TREM, TREM core fragment or TREM fragment species, wherein X=2, 3, 4, 5, 6, 7, 8, 9, or 10. In an embodiment, the TREM, TREM core fragment or TREM fragment has at least 70, 75, 80, 85, 90, or 95, or has 100%, identity with a sequence encoded by a nucleic acid in Table 1. A TREM composition can comprise one or more species of TREMs, TREM core fragments or TREM fragments. In an embodiment, the TREM composition is at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 95 or 99% dry weight TREMs (for a liquid composition dry weight refers to the weight after removal of substantially all liquid, e.g., after lyophilization). In an embodiment, the composition is a liquid. In an embodiment, the composition is dry, e.g., a WO 2024/216206 PCT/US2024/024492 lyophilized material. In an embodiment, the composition is a frozen composition. In an embodiment, the composition is sterile. In an embodiment, the composition comprises at least 0.5 g, 1.0 g, 5.0 g, 10 g, 15 g, 25 g, 50 g, 100 g, 200 g, 400 g, or 500 g (e.g., as determined by dry weight) of TREM. In an embodiment, at least X% of the TREMs in a TREM composition has a non-naturally occurring modification at a selected position, and X is 80, 90, 95, 96, 97, 98, 99, or 99.5.In an embodiment, at least X% of the TREMs in a TREM composition has a non- naturally occurring modification at a first position and a non-naturally occurring modification at a second position, and X, independently, is 80, 90, 95, 96, 97, 98, 99, or 99.5. In embodiments, the modification at the first and second position is the same. In embodiments, the modification at the first and second position are different. In embodiments, the nucleiotide at the first and second position is the same, e.g., both are adenine. In embodiments, the nucleiotide at the first and second position are different, e.g., one is adenine and one is thymine.In an embodiment, at least X% of the TREMs in a TREM composition has a non- naturally occurring modification at a first position and less than Y% have a non-naturally occurring modification at a second position, wherein X is 80, 90, 95, 96, 97, 98, 99, or 99.5 and Y is 20, 20, 5, 2, 1, .1, or .01. In embodiments, the nucleotide at the first and second position is the same, e.g., both are adenine. In embodiments the nucleotide at the first and second position are different, e.g., one is adenine and one is thymine.

TREM, TREM core fragment and TREM fragment A "tRNA-based effector molecule " or "TREM" refers to an RNA molecule comprising one or more of the properties described herein. A TREM can comprise a non-naturally occurring modification, e.g., as provided in Table 5. A TREM may further comprise a nucleotide modification, for example, a nucleotide substitution, nucleotide deletion, or nucleotide addition, relative to a second TREM.In an embodiment, a TREM includes a TREM comprising a sequence of Formula A; a TREM core fragment comprising a sequence of Formula B; or a TREM fragment comprising a portion of a TREM which TREM comprises a sequence of Formula A.

WO 2024/216206 PCT/US2024/024492 In an embodiment, a TREM comprises a sequence of Formula A: [Ll ]-[ASt Domainl]- [L2]-[DH Domain]-[L3]-[ACH Domain] -[VL Domain]-[TH D0main]-[L4]-[ASt Domain2]. In an embodiment, [VL Domain] is optional. In an embodiment, [Ll] is optional.In an embodiment, a TREM core fragment comprises a sequence of Formula B: [Ll] y- [ASt Domainl] X-[L2] y -[DH Domain] y -[L3] y -[ACH Domain] x -[VL Domain] y -[TH Domain] y - [L4] y -[ASt Domain2] x , wherein: x=l and y=0 or 1. In an embodiment, y=0. In an embodiment, y=L.In an embodiment, a TREM fragment comprises a portion of a TREM, wherein the TREM comprises a sequence of Formula A: [Ll]-[ASt Domainl]-[L2]-[DH Domain]-[L3]- [ACH Domain] -[VL Domain]-[TH Domain]-[L4]-[ASt Domain2], and wherein the TREM fragment comprises; one, two, three or all or any combination of the following: a TREM half (e.g., from a cleavage in the ACH Domain, e.g., in the anticodon sequence, e.g., a 5’half or a 3’ half); a 5’ fragment (e.g., a fragment comprising the 5’ end, e.g., from a cleavage in a DH Domain or the ACH Domain); a 3’ fragment (e.g, a fragment comprising the 3’ end, e.g., from a cleavage in the TH Domain); or an internal fragment (e.g, from a cleavage in any one of the ACH Domain, DH Domain or TH Domain). Exemplary TREM fragments include TREM halves (e.g, from a cleavage in the ACHD, e.g, 5’TREM halves or 3’ TREM halves), a 5’ fragment (e.g, a fragment comprising the 5’ end, e.g., from a cleavage in a DHD or the ACHD), a 3’ fragment (e.g, a fragment comprising the 3’ end of a TREM, e.g., from a cleavage in the THD), or an internal fragment (e.g, from a cleavage in one or more of the ACHD, DHD or THD).In an embodiment, a TREM, a TREM core fragment or a TREM fragment can be charged with an amino acid (e.g, a cognate amino acid); charged with a non-cognate amino acid (e.g, a mischarged TREM (mTREM)); or not charged with an amino acid (e.g, an uncharged TREM (uTREM)). In an embodiment, a TREM, a TREM core fragment or a TREM fragment can be charged with an amino acid selected from alanine, arginine, asparagine, aspartate, cysteine, glutamine, glutamate, glycine, histidine, isoleucine, methionine, leucine, lysine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine.In some embodiments, a non-extended anticodon is an anticodon of no more than three nucleotides. In an embodiment, a non-extended codon pairs with no more than three codon nucleotides on a nucleic acid being translated.

WO 2024/216206 PCT/US2024/024492 In an embodiment, the TREM, TREM core fragment or TREM fragment is a cognate TREM. In an embodiment, the TREM, TREM core fragment or TREM fragment is a non- cognate TREM. In an embodiment, the TREM, TREM core fragment or TREM fragment recognizes a codon provided in Table 2 or Table 3. Table 2:List of codons CUG cuu GAA GAC AAA GAGAAC GAUAAG GCAAAU GCCACA GCGACC GCUACG GGAACU GGCAGA GGGAGC GGUAGG GUAAGU GUCAUA GUGAUC GUUAUG UAAAUU UACCAA UAGCAC UAUCAG UCACAU UCCCCA UCGCCC UCUCCG UGACCU UGCCGA UGGCGC UGUCGG UUACGU UUCCUA UUGcue UUU WO 2024/216206 PCT/US2024/024492 Table 3:Amino acids and corresponding codons Amino Acid mRNA codons Alanine GCU, GCC, GCA, GCGArginine CGU, CGC, CGA, CGG, AGA, AGGAsparagine AAU, AACAspartate GAU, GACCysteine UGU, UGCGlutamate GAA, GAGGlutamine CAA, CAGGlycine GGU, GGC, GGA, GGGHistidine CAU, CACIsoleucine AUU, AUC, AUALeucine UUA, UUG, CUU, CUC, CUA, CUGLysine AAA, AAGMethionine AUGPhenylalanine UUU, UUCProline CCU, CCC, CCA, CCGSerine UCU, UCC, UCA, UCG, AGU, AGCStop UAA, UAG, UGAThreonine ACU, ACC, ACA, ACGTryptophanUGGTyrosine UAU, UACValine GUU, GUC, GUA, GUG In an embodiment, a TREM comprises a ribonucleic acid (RNA) sequence encoded by a deoxyribonucleic acid (DNA) sequence disclosed in Table 1, e.g, any one of SEQ ID NOs: 1- 451 disclosed in Table 1. In an embodiment, a TREM comprises an RNA sequence at least 60%, 65%, 70%, 75%, 80%, 82%, 85%, 87%, 88%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to an RNA sequence encoded by a DNA sequence provided in Table 1, e.g., any one of SEQ ID NOs: 1-451 disclosed in Table 1. In an embodiment, a TREM comprises an RNA sequence encoded by a DNA sequence at least 60%, 65%, 70%, 75%, 80%, 82%, 85%, 87%, 88%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to a DNA sequence provided in Table 1, e.g., any one of SEQ ID NOs: 1-451 disclosed in Table 1.In an embodiment, a TREM, a TREM core fragment, or TREM fragment comprises at least 5, 10, 15, 20, 25, or 30 consecutive nucleotides of an RNA sequence encoded by a DNA WO 2024/216206 PCT/US2024/024492 sequence disclosed in Table 1, e.g., at least 5, 10, 15, 20, 25, or 30 consecutive nucleotides of an RNA sequence encoded by any one of SEQ ID NOs: 1-451 disclosed in Table 1. In an embodiment, a TREM, a TREM core fragment, or TREM fragment comprises at least 5, 10, 15, 20, 25, or 30 consecutive nucleotides of an RNA sequence at least 60%, 65%, 70%, 75%, 80%, 82%, 85%, 87%, 88%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to an RNA sequence encoded by aDNA sequence provided in Table 1, e.g, any one of SEQ ID NOs: 1-451 disclosed in Table 1. In an embodiment, a TREM, a TREM core fragment, or TREM fragment comprises at least 5, 10, 15, 20, 25, or 30 consecutive nucleotides of an RNA sequence encoded by a DNA sequence at least 60%, 65%, 70%, 75%, 80%, 82%, 85%, 87%, 88%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to a DNA sequence provided in Table 1, e.g., any one of SEQ ID NOs: 1-451 disclosed in Table 1.In an embodiment, a TREM core fragment or a TREM fragment comprises at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% of an RNA sequence encoded by a DNA sequence provided in Table 1, e.g., any one of SEQ ID NOs: 1-451 disclosed in Table 1. In an embodiment, a TREM core fragment or a TREM fragment comprises at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% of an RNA sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to an RNA sequence encoded by a DNA sequence provided in Table 1, e.g., any one of SEQ ID NOs: 1-4disclosed in Table 1. In an embodiment, a TREM core fragment or a TREM fragment comprises at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% of an RNA sequence encoded by aDNA sequence at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to a DNA sequence provided in Table 1, e.g., any one of SEQ ID NOs: 1-451 disclosed in Table 1.In an embodiment, a TREM core fragment or a TREM fragment comprises at least ribonucleotides (nt), 10 nt, 15 nt, 20 nt, 25 nt, 30 nt, 35 nt, 40 nt, 45 nt, 50 nt, 55 nt or 60 nt (but less than the full length) of an RNA sequence encoded by a DNA sequence disclosed in Table 1, e.g., any one of SEQ ID NOs: 1-451 disclosed in Table 1. In an embodiment, a TREM core fragment or a TREM fragment comprises at least 5 ribonucleotides (nt), 10 nt, 15 nt, 20 nt, 25 nt, nt, 35 nt, 40 nt, 45 nt, 50 nt, 55 nt or 60 nt (but less than the full length) of an RNA sequence which is at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to an RNA WO 2024/216206 PCT/US2024/024492 sequence encoded by a DNA sequence provided in Table 1, e.g., any one of SEQ ID NOs: 1-4disclosed in Table 1. In an embodiment, a TREM core fragment or a TREM fragment comprises at least 5 ribonucleotides (nt), 10 nt, 15 nt, 20 nt, 25 nt, 30 nt, 35 nt, 40 nt, 45 nt, 50 nt, 55 nt or nt (but less than the full length) of an RNA sequence encoded by a DNA sequence with at least 80%, 82%, 85%, 87%, 88%, 90%, 92%, 95%, 96%, 97%, 98%, 99% or 100% identity to a DNA sequence provided in Table 1, e.g, any one of SEQ ID NOs: 1-451 disclosed in Table 1.In an embodiment, a TREM core fragment or a TREM fragment comprises a sequence of a length of between 10-90 ribonucleotides (mt), between 10-80 rnt, between 10-70 rt, between 10-60 rnt, between 10-50 rnt, between 10-40 rnt, between 10-30 rnt, between 10-20 rnt, between 20-90 rnt, between 20-80 rnt, 20-70 rnt, between 20-60 rnt, between 20-50 rnt, between 20-rnt, between 30-90 rnt, between 30-80 rnt, between 30-70 rnt, between 30-60 rnt, or between 30- rnt Table 1:List of tRNA Sequences SEQ ID NO tRNA name tRNA sequence 1 Ala_AGC_chr6 :287741-28763812 (-)GGGGGTATAGCTCAGTGGTAGAGCGCGTGCT TAGCATGCACGAGGTCCTGGGTTCGATCCCC AGTACCTCCA 2 Ala_AGC_chr6:266485-26687557 (+)GGGGAATTAGCTCAAGTGGTAGAGCGCTTGC TTAGCACGCAAGAGGTAGTGGGATCGATGCC CACATTCTCCAAla_AGC_chr6:265092-26572164 (-)GGGGAATTAGCTCAAATGGTAGAGCGCTCGC TTAGCATGCGAGAGGTAGCGGGATCGATGCC CGCATTCTCCA 4 Ala_AGC_chr6 :266715-26682787 (+)GGGGAATTAGCTCAAGTGGTAGAGCGCTTGC TTAGCATGCAAGAGGTAGTGGGATCGATGCC CACATTCTCCAAla_AGC_chr6 :267606-26705678 (+)GGGGAATTAGCTCAAGCGGTAGAGCGCTTGC TTAGCATGCAAGAGGTAGTGGGATCGATGCC CACATTCTCCAAla_AGC_chr6:266590-26673662 (+)GGGGAATTAGCTCAAGTGGTAGAGCGCTTGC TTAGCATGCAAGAGGTAGTGGGATCAATGCC CACATTCTCCA WO 2024/216206 PCT/US2024/024492 7 Ala_AGC_chrl4:895442-89445514(+)GGGGAATTAGCTCAAGTGGTAGAGCGCTCGC TTAGCATGCGAGAGGTAGTGGGATCGATGCC CGCATTCTCCAAla_AGC_chr6:581623-58196695 (-)GGGGAATTAGCCCAAGTGGTAGAGCGCTTGC TTAGCATGCAAGAGGTAGTGGGATCGATGCC CACATTCTCCA 9 Ala_AGC_chr6:288221-28806292 (-)GGGGGTGTAGCTCAGTGGTAGAGCGCGTGCT TAGCATGCACGAGGCCCCGGGTTCAATCCCC GGCACCTCCAAla_AGC_chr6:285933-28575004 (+)GGGGGTGTAGCTCAGTGGTAGAGCGCGTGCT TAGCATGTACGAGGTCCCGGGTTCAATCCCC GGCACCTCCAAla_AGC_chr6:286014-28626085 (-)GGGGATGTAGCTCAGTGGTAGAGCGCATGCT TAGCATGCATGAGGTCCCGGGTTCGATCCCC AGCATCTCCAAla_AGC_chr6:286366-28678437 (+)GGGGGTGTAGCTCAGTGGTAGAGCGCGTGCT TAGCATGCACGAGGCCCTGGGTTCAATCCCC AGCACCTCCAAla_AGC_chr6 :287849-28779920 (-)GGGGGTATAGCTCAGCGGTAGAGCGCGTGCT TAGCATGCACGAGGTCCTGGGTTCAATCCCC AATACCTCCAAla_AGC_chr6:286481-28687552 (+)GGGGGTGTAGCTCAGTGGTAGAGCGCGTGCT TAGCATGCACGAGGCCCCGGGTTCAATCCCT GGCACCTCCAAla_AGC_chr2:272082-27274154 (+)GGGGGATTAGCTCAAATGGTAGAGCGCTCGC TTAGCATGCGAGAGGTAGCGGGATCGATGCC CGCATCCTCCAAla_AGC_chr6 :267737-26730809 (+)GGGGAATTAGCTCAGGCGGTAGAGCGCTCGC TTAGCATGCGAGAGGTAGCGGGATCGACGCC CGCATTCTCCAAla_CGC_chr6:265731-26553802 (+)GGGGATGTAGCTCAGTGGTAGAGCGCATGCT TCGCATGTATGAGGTCCCGGGTTCGATCCCC GGCATCTCCAAla_CGC_chr6:286613-28641684 (-)GGGGATGTAGCTCAGTGGTAGAGCGCATGCT TCGCATGTATGAGGCCCCGGGTTCGATCCCC GGCATCTCCA WO 2024/216206 PCT/US2024/024492 19 Ala_CGC_chr2: 1577281-157257352 (+)GGGGATGTAGCTCAGTGGTAGAGCGCGCGCT TCGCATGTGTGAGGTCCCGGGTTCAATCCCC GGCATCTCCAAla_CGC_chr6:286092-28697163 (+)GGGGGTGTAGCTCAGTGGTAGAGCGCGTGCT TCGCATGTACGAGGCCCCGGGTTCGACCCCC GGCTCCTCCAAla_TGC_chr6:287547-28757618 (-)GGGGGTGTAGCTCAGTGGTAGAGCGCATGCT TTGCATGTATGAGGTCCCGGGTTCGATCCCC GGCACCTCCAAla_TGC_chr6:2861 222-28611293 (+)GGGGATGTAGCTCAGTGGTAGAGCGCATGCT TTGCATGTATGAGGTCCCGGGTTCGATCCCC GGCATCTCCAAla_TGC_chr5: 1803868-180633939 (+)GGGGATGTAGCTCAGTGGTAGAGCGCATGCT TTGCATGTATGAGGCCCCGGGTTCGATCCCC GGCATCTCCAAla_TGC_chrl2:1224512-125424583 (+)GGGGATGTAGCTCAGTGGTAGAGCGCATGCT TTGCACGTATGAGGCCCCGGGTTCAATCCCC GGCATCTCCAAla_TGC_chr6:287012-28785083 (-)GGGGGTGTAGCTCAGTGGTAGAGCGCATGCT TTGCATGTATGAGGCCTCGGGTTCGATCCCC GACACCTCCAAla_TGC_chr6;287141-28726212 (-)GGGGGTGTAGCTCAGTGGTAGAGCACATGCTTTGCATGTGTGAGGCCCCGGGTTCGATCCCC GGCACCTCCAAla_TGC_chr6: 287577-28770647 (-)GGGGGTGTAGCTCAGTGGTAGAGCGCATGCT TTGCATGTATGAGGCCTCGGTTCGATCCCCG ACACCTCCAArg_ACG_chr6 :263368-26328440 (+)GGGCCAGTGGCGCAATGGATAACGCGTCTGA CTACGGATCAGAAGATTCCAGGTTCGACTCC TGGCTGGCTCGArg_ACG_chr3 :457491-45730563 (-)GGGCCAGTGGCGCAATGGATAACGCGTCTGA CTACGGATCAGAAGATTCTAGGTTCGACTCC TGGCTGGCTCGArg_CCG_chr6:287729-28710801 (-)GGCCGCGTGGCCTAATGGATAAGGCGTCTGA TTCCGGATCAGAAGATTGAGGGTTCGAGTCC CTTCGTGGTCGArg_CCG_chrl7:666013-66016085 (-)GACCCAGTGGCCTAATGGATAAGGCATCAGC CTCCGGAGCTGGGGATTGTGGGTTCGAGTCC CATCTGGGTCG WO 2024/216206 PCT/US2024/024492 32 Arg_CCT_chr 17:730001-73030073 (+)GCCCCAGTGGCCTAATGGATAAGGCACTGGC CTCCTAAGCCAGGGATTGTGGGTTCGAGTCC CACCTGGGGTAArg_CCT_chrl7:730526-73030598 (-)GCCCCAGTGGCCTAATGGATAAGGCACTGGC CTCCTAAGCCAGGGATTGTGGGTTCGAGTCC CACCTGGGGTGArg_CCT_chrl6:32901-3202973 (+)GCCCCGGTGGCCTAATGGATAAGGCATTGGC CTCCTAAGCCAGGGATTGTGGGTTCGAGTCC CACCCGGGGTAArg_CCT_chr7: 1395446-139025518 (+)GCCCCAGTGGCCTAATGGATAAGGCATTGGC CTCCTAAGCCAGGGATTGTGGGTTCGAGTCC CATCTGGGGTGArg_CCT_chrl6:32918-3243990 (+)GCCCCAGTGGCCTGATGGATAAGGTACTGGC CTCCTAAGCCAGGGATTGTGGGTTCGAGTTC CACCTGGGGTA 37 Arg_TCG_chrl5:898304-89878376 (+)GGCCGCGTGGCCTAATGGATAAGGCGTCTGACTTCGGATCAGAAGATTGCAGGTTCGAGTCC TGCCGCGGTCG 38 Arg_TCG_chr6:263046-26323118(+)GACCACGTGGCCTAATGGATAAGGCGTCTGA CTTCGGATCAGAAGATTGAGGGTTCGAATCC CTCCGTGGTTAArg_TCG_chr 17:731208-73031280(+)GACCGCGTGGCCTAATGGATAAGGCGTCTGA CTTCGGATCAGAAGATTGAGGGTTCGAGTCC CTTCGTGGTCGArg_TCG_chr6 :262905-26299977 (+)GACCACGTGGCCTAATGGATAAGGCGTCTGA CTTCGGATCAGAAGATTGAGGGTTCGAATCC CTTCGTGGTTAArg_TCG_chr6:285891-28510963 (-)GACCACGTGGCCTAATGGATAAGGCGTCTGA CTTCGGATCAGAAGATTGAGGGTTCGAATCC CTTCGTGGTTGArg_TCG_chr9: 1120803-112960875 (+)GGCCGTGTGGCCTAATGGATAAGGCGTCTGA CTTCGGATCAAAAGATTGCAGGTTTGAGTTC TGCCACGGTCGArg_TCT_chrl:94313129-94313213 (+)GGCTCCGTGGCGCAATGGATAGCGCATTGGA CTTCTAGAGGCTGAAGGCATTCAAAGGTTCC GGGTTCGAGTCCCGGCGGAGTCG WO 2024/216206 PCT/US2024/024492 44 Arg_TCT_chrl7:80243-8024330 (+)GGCTCTGTGGCGCAATGGATAGCGCATTGGA CTTCTAGTGACGAATAGAGCAATTCAAAGGT TGTGGGTTCGAATCCCACCAGAGTCGArg_TCT_chr9:1312355-131102445 (-)GGCTCTGTGGCGCAATGGATAGCGCATTGGA CTTCTAGCTGAGCCTAGTGTGGTCATTCAAA GGTTGTGGGTTCGAGTCCCACCAGAGTCGArgTCTchrl 1:59318767-59318852 (+)GGCTCTGTGGCGCAATGGATAGCGCATTGGA CTTCTAGATAGTTAGAGAAATTCAAAGGTTG TGGGTTCGAGTCCCACCAGAGTCGArgTCTchrl: 159111401-159111474 (-)GTCTCTGTGGCGCAATGGACGAGCGCGCTGG ACTTCTAATCCAGAGGTTCCGGGTTCGAGTC CCGGCAGAGATGArg_TCT_chr6:275963-27530049 (+)GGCTCTGTGGCGCAATGGATAGCGCATTGGA CTTCTAGCCTAAATCAAGAGATTCAAAGGTT GCGGGTTCGAGTCCCTCCAGAGTCGAsnGTTchrl :1610031-161510104 (+)GTCTCTGTGGCGCAATCGGTTAGCGCGTTCG GCTGTTAACCGAAAGGTTGGTGGTTCGATCC CACCCAGGGACGAsnGTTchrl: 1439832-143879905 (-)GTCTCTGTGGCGCAATCGGCTAGCGCGTTTG GCTGTTAACTAAAAGGTTGGCGGTTCGAACC CACCCAGAGGCGAsnGTTchrl: 144301611-144301684 (+)GTCTCTGTGGTGCAATCGGTTAGCGCGTTCCG CTGTTAACCGAAAGCTTGGTGGTTCGAGCCC ACCCAGGGATGAsnGTTchrl: 1496272-149326345 (-)GTCTCTGTGGCGCAATCGGCTAGCGCGTTTG GCTGTTAACTAAAAAGTTGGTGGTTCGAACA CACCCAGAGGCGAsnGTTchrl: 148248115-148248188 (+)GTCTCTGTGGCGCAATCGGTTAGCGCGTTCG GCTGTTAACCGAAAGGTTGGTGGTTCGAGCC CACCCAGGGACGAsnGTTchrl: 1488314-148598387 (-)GTCTCTGTGGCGCAATCGGTTAGCGCATTCG GCTGTTAACCGAAAGGTTGGTGGTTCGAGCC CACCCAGGGACGAsnGTTchrl: 172172-17216245 (+)GTCTCTGTGGCGCAATCGGTTAGCGCGTTCG GCTGTTAACCGAAAGATTGGTGGTTCGAGCC CACCCAGGGACG WO 2024/216206 PCT/US2024/024492 56 Asn_GTT_chrl: 16847080-16847153 (-)GTCTCTGTGGCGCAATCGGTTAGCGCGTTCG GCTGTTAACTGAAAGGTTGGTGGTTCGAGCC CACCCAGGGACGAsnGTTchrl: 149230570-149230643 (-)GTCTCTGTGGCGCAATGGGTTAGCGCGTTCG GCTGTTAACCGAAAGGTTGGTGGTTCGAGCC CATCCAGGGACGAsnGTTchrl: 1480805-148000878 (+)GTCTCTGTGGCGTAGTCGGTTAGCGCGTTCG GCTGTTAACCGAAAAGTTGGTGGTTCGAGCC CACCCAGGAACGAsnGTTchrl: 1491798-149711871 (-)GTCTCTGTGGCGCAATCGGCTAGCGCGTTTG GCTGTTAACTAAAAGGTTGGTGGTTCGAACC CACCCAGAGGCGAsnGTTchrl: 1459034-145979107 (-)GTCTCTGTGGCGCAATCGGTTAGCGCGTTCGGCTGTTAACTGAAAGGTTAGTGGTTCGAGCC CACCCGGGGACGAsp_GTC_chrl2:987281-98897352 (+)TCCTCGTTAGTATAGTGGTTAGTATCCCCGCC TGTCACGCGGGAGACCGGGGTTCAATTCCCC GACGGGGAGAspGTCchrl: 161410615-161410686 (-)TCCTCGTTAGTATAGTGGTGAGTATCCCCGCC TGTCACGCGGGAGACCGGGGTTCGATTCCCC GACGGGGAGAsp_GTC_chr6:275236-27551307 (-)TCCTCGTTAGTATAGTGGTGAGTGTCCCCGTC TGTCACGCGGGAGACCGGGGTTCGATTCCCC GACGGGGAGCys_GCA_chr7: 1497281-149007352 (+)GGGGGCATAGCTCAGTGGTAGAGCATTTGAC TGCAGATCAAGAGGTCCCTGGTTCAAATCCA GGTGCCCCCTCys_GCA_chr7: 1494601-149074672 (-)GGGGGTATAGCTCAGGGGTAGAGCATTTGAC TGCAGATCAAGAGGTCCCTGGTTCAAATCCA GGTGCCCCCCCys_GCA_chr7: 1492229-149112300 (-)GGGGGTATAGCTTAGCGGTAGAGCATTTGAC TGCAGATCAAGAGGTCCCCGGTTCAAATCCG GGTGCCCCCTCys_GCA_chr7: 1494046-149344117 (-)GGGGGTATAGCTTAGGGGTAGAGCATTTGAC TGCAGATCAAAAGGTCCCTGGTTCAAATCCA GGTGCCCCTT WO 2024/216206 PCT/US2024/024492 68 Cys_GCA_chr7: 1492766-149052837 (-)GGGGGTATAGCTCAGGGGTAGAGCATTTGAC TGCAGATCAAGAGGTCCCCAGTTCAAATCTG GGTGCCCCCTCys_GCA_chrl 7:377937-37018008 (-)GGGGGTATAGCTCAGGGGTAGAGCATTTGAC TGCAGATCAAGAAGTCCCCGGTTCAAATCCG GGTGCCCCCTCys_GCA_chr7: 1491816-149281887 (+)GGGGGTATAGCTCAGGGGTAGAGCATTTGAC TGCAGATCAAGAGGTCTCTGGTTCAAATCCA GGTGCCCCCTCys_GCA_chr7: 1493631-149243702 (+)GGGGGTATAGCTCAGGGGTAGAGCACTTGAC TGCAGATCAAGAAGTCCTTGGTTCAAATCCA GGTGCCCCCTCys_GCA_chr7: 1498272-149388343 (-)GGGGATATAGCTCAGGGGTAGAGCATTTGAC TGCAGATCAAGAGGTCCCCGGTTCAAATCCG GGTGCCCCCCCys_GCA_chr7: 1492850-149072921 (-)GGGGGTATAGTTCAGGGGTAGAGCATTTGAC TGCAGATCAAGAGGTCCCTGGTTCAAATCCA GGTGCCCCCTCys_GCA_chr7: 1490156-149310227 (-)GGGGGTATAGCTCAGGGGTAGAGCATTTGAC TGCAAATCAAGAGGTCCCTGATTCAAATCCA GGTGCCCCCTCys_GCA_chr4: 1240005-124430076 (-)GGGGGTATAGCTCAGTGGTAGAGCATTTGAC TGCAGATCAAGAGGTCCCCGGTTCAAATCCG GGTGCCCCCTCys_GCA_chr7: 1495046-149295117 (+)GGGCGTATAGCTCAGGGGTAGAGCATTTGAC TGCAGATCAAGAGGTCCCCAGTTCAAATCTG GGTGCCCCCTCys_GCA_chr7: 1491915-149361986 (+)GGGGGTATAGCTCACAGGTAGAGCATTTGAC TGCAGATCAAGAGGTCCCCGGTTCAAATCTG GGTGCCCCCTCys GCA chr7: 1493802-149253871 (+)GGGCGTATAGCTCAGGGGTAGAGCATTTGAC TGCAGATCAAGAGGTCCCCAGTTCAAATCTG GGTGCCCACys_GCA_chr7: 1492305-149292376 (-)GGGGGTATAGCTCACAGGTAGAGCATTTGAC TGCAGATCAAGAGGTCCCCGGTTCAAATCCG GTTACTCCCTCys_GCA_chr7: 1496164-149286235 (-)GGGGGTATAGCTCAGGGGTAGAGCACTTGAC TGCAGATCAAGAGGTCCCTGGTTCAAATCCA GGTGCCCCCT WO 2024/216206 PCT/US2024/024492 81 Cys_GCA_chrl 7:375545-37025616 (-)GGGGGTATAGCTCAGTGGTAGAGCATTTGAC TGCAGATCAAGAGGTCCCTGGTTCAAATCCG GGTGCCCCCTCys_GCA_chrl5:806997-80037069 (+)GGGGGTATAGCTCAGTGGGTAGAGCATTTGA CTGCAGATCAAGAGGTCCCCGGTTCAAATCC GGGTGCCCCCTCys_GCA_chr3:1317944-131948015 (-)GGGGGTGTAGCTCAGTGGTAGAGCATTTGAC TGCAGATCAAGAGGTCCCTGGTTCAAATCCA GGTGCCCCCTCys_GCA_chrl :93981834-93981906 (-)GGGGGTATAGCTCAGGTGGTAGAGCATTTGA CTGCAGATCAAGAGGTCCCCGGTTCAAATCC GGGTGCCCCCTCys_GCA_chr 14:73 9679-73429750 (+)GGGGGTATAGCTCAGGGGTAGAGCATTTGAC TGCAGATCAAGAGGTCCCCGGTTCAAATCCG GGTGCCCCCTCys_GCA_chr3:1310642-131950713 (-)GGGGGTATAGCTCAGGGGTAGAGCATTTGAC TGCAGATCAAGAGGTCCCTGGTTCAAATCCA GGTGCCCCCTGln_CTG_chr6: 188402-18836473 (+)GGTTCCATGGTGTAATGGTTAGCACTCTGGA CTCTGAATCCAGCGATCCGAGTTCAAATCTC GGTGGAACCTGln_CTG_chr6:275531-27515602 (-)GGTTCCATGGTGTAATGGTTAGCACTCTGGA CTCTGAATCCAGCGATCCGAGTTCAAGTCTC GGTGGAACCTGlnCTGchrl: 1453304-145963375 (+)GGTTCCATGGTGTAATGGTGAGCACTCTGGA CTCTGAATCCAGCGATCCGAGTTCGAGTCTC GGTGGAACCTGlnCTGchrl: 1477382-147737453 (-)GGTTCCATGGTGTAATGGTAAGCACTCTGGA CTCTGAATCCAGCGATCCGAGTTCGAGTCTC GGTGGAACCTGin CTG chr6: 272212-27263283 (+)GGTTCCATGGTGTAATGGTTAGCACTCTGGA CTCTGAATCCGGTAATCCGAGTTCAAATCTC GGTGGAACCTGln_CTG_chr6:277135-27759206 (-)GGCCCCATGGTGTAATGGTCAGCACTCTGGA CTCTGAATCCAGCGATCCGAGTTCAAATCTC GGTGGGACCCGln_CTG_chrl: 147800937-147801008 (+)GGTTCCATGGTGTAATGGTAAGCACTCTGGA CTCTGAATCCAGCCATCTGAGTTCGAGTCTCT GTGGAACCT WO 2024/216206 PCT/US2024/024492 94 Gln_TTG_chrl 7:479890-47269961 (+)GGTCCCATGGTGTAATGGTTAGCACTCTGGA CTTTGAATCCAGCGATCCGAGTTCAAATCTC GGTGGGACCTGln_TTG_chr6:285156-28557227 (+)GGTCCCATGGTGTAATGGTTAGCACTCTGGA CTTTGAATCCAGCAATCCGAGTTCGAATCTC GGTGGGACCTGln_TTG_chr6:2631 424-26311495 (-)GGCCCCATGGTGTAATGGTTAGCACTCTGGA CTTTGAATCCAGCGATCCGAGTTCAAATCTC GGTGGGACCTGln_TTG_chr6: 1453859-145503930 (+)GGTCCCATGGTGTAATGGTTAGCACTCTGGG CTTTGAATCCAGCAATCCGAGTTCGAATCTTG GTGGGACCTGluCTCchrl: 145399233-145399304 (-)TCCCTGGTGGTCTAGTGGTTAGGATTCGGCGCTCTCACCGCCGCGGCCCGGGTTCGATTCCC GGTCAGGGAAGluCTCchrl :249168447-249168518 (+)TCCCTGGTGGTCTAGTGGTTAGGATTCGGCGCTCTCACCGCCGCGGCCCGGGTTCGATTCCC GGTCAGGAAA100 Glu_TTC_chr2:1314701-131094772 (-)TCCCATATGGTCTAGCGGTTAGGATTCCTGGT TTTCACCCAGGTGGCCCGGGTTCGACTCCCG GTATGGGAA101 Glu TTC chrl3:452062-45492133 (-)TCCCACATGGTCTAGCGGTTAGGATTCCTGGT TTTCACCCAGGCGGCCCGGGTTCGACTCCCG GTGTGGGAA102 GluTTCchrl: 171078-17199149 (+)TCCCTGGTGGTCTAGTGGCTAGGATTCGGCG CTTTCACCGCCGCGGCCCGGGTTCGATTCCCG GCCAGGGAA103 GluTTCchrl: 168774-16861845 (-)TCCCTGGTGGTCTAGTGGCTAGGATTCGGCG CTTTCACCGCCGCGGCCCGGGTTCGATTCCCG GTCAGGGAA104 GlyCCCchrl: 168434-16872504 (-)GCATTGGTGGTTCAGTGGTAGAATTCTCGCCT CCCACGCGGGAGACCCGGGTTCAATTCCCGG CCAATGCA105 Gly_CCC_chr2: 704123-70476193 (-)GCGCCGCTGGTGTAGTGGTATCATGCAAGAT TCCCATTCTTGCGACCCGGGTTCGATTCCCGGGCGGCGCA106 Gly_CCC_chrl7:194175-19764245 (+)GCATTGGTGGTTCAATGGTAGAATTCTCGCCT CCCACGCAGGAGACCCAGGTTCGATTCCTGG CCAATGCA WO 2024/216206 PCT/US2024/024492 107 GlyGCCchrl: 1613094-161413164 (+)GCATGGGTGGTTCAGTGGTAGAATTCTCGCC TGCCACGCGGGAGGCCCGGGTTCGATTCCCG GCCCATGCA108 GlyGCCchrl: 161493637-161493707 (-)GCATTGGTGGTTCAGTGGTAGAATTCTCGCCT GCCACGCGGGAGGCCCGGGTTCGATTCCCGG CCAATGCA109 Gly_GCC_chrl6:702114-70812184 (-)GCATTGGTGGTTCAGTGGTAGAATTCTCGCCT GCCACGCGGGAGGCCCGGGTTTGATTCCCGG CCAGTGCA110 GlyGCCchrl: 1610356-161450426 (+)GCATAGGTGGTTCAGTGGTAGAATTCTTGCC TGCCACGCAGGAGGCCCAGGTTTGATTCCTG GCCCATGCAill Gly_GCC_chrl6:702597-70822667 (+)GCATTGGTGGTTCAGTGGTAGAATTCTCGCCT GCCATGCGGGCGGCCGGGCTTCGATTCCTGG CCAATGCA112 Gly_TCC_chrl9:47082-4724153 (+)GCGTTGGTGGTATAGTGGTTAGCATAGCTGC CTTCCAAGCAGTTGACCCGGGTTCGATTCCC GGCCAACGCA113 GlyTCCchrl: 1457864-145397935 (-)GCGTTGGTGGTATAGTGGTGAGCATAGCTGC CTTCCAAGCAGTTGACCCGGGTTCGATTCCC GGCCAACGCA114 Gly_TCC_chrl7:81866-8124937 (+)GCGTTGGTGGTATAGTGGTAAGCATAGCTGC CTTCCAAGCAGTTGACCCGGGTTCGATTCCC GGCCAACGCA115 GlyTCCchrl; 1619961-161410032 (-)GCGTTGGTGGTATAGTGGTGAGCATAGTTGC CTTCCAAGCAGTTGACCCGGGCTCGATTCCC GGCCAACGCA116 HisGTGchrl: 145396881-145396952 (-)GCCGTGATCGTATAGTGGTTAGTACTCTGCGT TGTGGCCGCAGCAACCTCGGTTCGAATCCGA GTCACGGCA117 HisGTGchrl: 149155828-149155899 (-)GCCATGATCGTATAGTGGTTAGTACTCTGCG CTGTGGCCGCAGCAACCTCGGTTCGAATCCG AGTCACGGCA118 Ile_AAT_chr6:581454-58149327 (+)GGCCGGTTAGCTCAGTTGGTTAGAGCGTGGC GCTAATAACGCCAAGGTCGCGGGTTCGATCC CCGTACGGGCCA119 Ile_AAT_chr6:276567-27656040 (+)GGCCGGTTAGCTCAGTTGGTTAGAGCGTGGT GCTAATAACGCCAAGGTCGCGGGTTCGATCC CCGTACTGGCCA WO 2024/216206 PCT/US2024/024492 120 Ile_AAT_chr6:272490-27243063 (-)GGCTGGTTAGCTCAGTTGGTTAGAGCGTGGT GCTAATAACGCCAAGGTCGCGGGTTCGATCC CCGTACTGGCCA121 Ile_AAT_chrl7:81309-8130382 (-)GGCCGGTTAGCTCAGTTGGTTAGAGCGTGGT GCTAATAACGCCAAGGTCGCGGGTTCGAACC CCGTACGGGCCA122 Ile_AAT_chr6:265550-26554423 (+)GGCCGGTTAGCTCAGTTGGTTAGAGCGTGGT GCTAATAACGCCAAGGTCGCGGGTTCGATCC CCGTACGGGCCA123 Ile_AAT_chr6:267455-26745328 (-)GGCCGGTTAGCTCAGTTGGTTAGAGCGTGGT GCTAATAACGCTAAGGTCGCGGGTTCGATCC CCGTACTGGCCA124 Ile_AAT_chr6:267221-26721294 (-)GGCCGGTTAGCTCAGTTGGTCAGAGCGTGGT GCTAATAACGCCAAGGTCGCGGGTTCGATCC CCGTACGGGCCA125 Ile_AAT_chr6:276362-27636435 (+)GGCCGGTTAGCTCAGTCGGCTAGAGCGTGGT GCTAATAACGCCAAGGTCGCGGGTTCGATCC CCGTACGGGCCA126 Ile_AAT_chr6:272439-27241812 (+)GGCTGGTTAGTTCAGTTGGTTAGAGCGTGGT GCTAATAACGCCAAGGTCGTGGGTTCGATCC CCATATCGGCCA127 Ile_GAT_chrX:37518-3756491 (-)GGCCGGTTAGCTCAGTTGGTAAGAGCGTGGT GCTGATAACACCAAGGTCGCGGGCTCGACTC CCGCACCGGCCA128 Ile_TAT_chrl9:399808-39902900 (-)GCTCCAGTGGCGCAATCGGTTAGCGCGCGGT ACTTATATGACAGTGCGAGCGGAGCAATGCC GAGGTTGTGAGTTCGATCCTCACCTGGAGCA 129 Ile_TAT_chr2:430376-43037768(+)GCTCCAGTGGCGCAATCGGTTAGCGCGCGGT ACTTATACAGCAGTACATGCAGAGCAATGCC GAGGTTGTGAGTTCGAGCCTCACCTGGAGCA130 Ile_TAT_chr6:269825-26988218 (+)GCTCCAGTGGCGCAATCGGTTAGCGCGCGGT ACTTATATGGCAGTATGTGTGCGAGTGATGC CGAGGTTGTGAGTTCGAGCCTCACCTGGAGC A131 Ile_TAT_chr6:275900-27599293 (+)GCTCCAGTGGCGCAATCGGTTAGCGCGCGGT ACTTATACAACAGTATATGTGCGGGTGATGC CGAGGTTGTGAGTTCGAGCCTCACCTGGAGC A WO 2024/216206 PCT/US2024/024492 132 Ile_TAT_chr6:285067-28505460 (+)GCTCCAGTGGCGCAATCGGTTAGCGCGCGGT ACTTATAAGACAGTGCACCTGTGAGCAATGC CGAGGTTGTGAGTTCAAGCCTCACCTGGAGC A 133 Leu_AAG_chr5 :180524474-180524555 (-)GGTAGCGTGGCCGAGCGGTCTAAGGCGCTGG ATTAAGGCTCCAGTCTCTTCGGAGGCGTGGG TTCGAATCCCACCGCTGCCA134 Leu_AAG_chr5 :1814701-180614782 (+)GGTAGCGTGGCCGAGCGGTCTAAGGCGCTGG ATTAAGGCTCCAGTCTCTTCGGGGGCGTGGG TTCGAATCCCACCGCTGCCA135 Leu_AAG_chr6:286779-28956860 (+)GGTAGCGTGGCCGAGCGGTCTAAGGCGCTGG ATTAAGGCTCCAGTCTCTTCGGGGGCGTGGG TTCAAATCCCACCGCTGCCA136 Leu_AAG_chr6:286400-28446481 (-)GGTAGCGTGGCCGAGTGGTCTAAGACGCTGG ATTAAGGCTCCAGTCTCTTCGGGGGCGTGGG TTTGAATCCCACCGCTGCCA137 Leu_CAA_chr6:288000-28864105 (-)GTCAGGATGGCCGAGTGGTCTAAGGCGCCAG ACTCAAGCTAAGCTTCCTCCGCGGTGGGGAT TCTGGTCTCCAATGGAGGCGTGGGTTCGAAT CCCACTTCTGACA138 Leu_CAA_chr6:289830-28908934 (+)GTCAGGATGGCCGAGTGGTCTAAGGCGCCAG ACTCAAGCTTGGCTTCCTCGTGTTGAGGATTC TGGTCTCCAATGGAGGCGTGGGTTCGAATCC CACTTCTGACA139 Leu_CAA_chr6:275417-27573524 (-)GTCAGGATGGCCGAGTGGTCTAAGGCGCCAG ACTCAAGCTTACTGCTTCCTGTGTTCGGGTCT TCTGGTCTCCGTATGGAGGCGTGGGTTCGAA TCCCACTTCTGACA140 Leu_CAA_chr6:275348-27570454 (-)GTCAGGATGGCCGAGTGGTCTAAGGCGCCAG ACTCAAGTTGCTACTTCCCAGGTTTGGGGCTT CTGGTCTCCGCATGGAGGCGTGGGTTCGAAT CCCACTTCTGACA141 Leu_CAA_chrl:249168054-249168159 (+)GTCAGGATGGCCGAGTGGTCTAAGGCGCCAG ACTCAAGGTAAGCACCTTGCCTGCGGGCTTT CTGGTCTCCGGATGGAGGCGTGGGTTCGAAT CCCACTTCTGACA142 LeuCAAchrl 1:9296790-9296863 (+)GCCTCCTTAGTGCAGTAGGTAGCGCATCAGT CTCAAAATCTGAATGGTCCTGAGTTCAAGCC TCAGAGGGGGCA WO 2024/216206 PCT/US2024/024492 143 Leu_CAA_chrl: 161581736-161581819 (-)GTCAGGATGGCCGAGCAGTCTTAAGGCGCTG CGTTCAAATCGCACCCTCCGCTGGAGGCGTG GGTTCGAATCCCACTTTTGACA144 LeuCAGchrl: 161411323-161411405 (+)GTCAGGATGGCCGAGCGGTCTAAGGCGCTGC GTTCAGGTCGCAGTCTCCCCTGGAGGCGTGG GTTCGAATCCCACTCCTGACA145 Leu_CAG_chrl6;573863-57333945 (+)GTCAGGATGGCCGAGCGGTCTAAGGCGCTGC GTTCAGGTCGCAGTCTCCCCTGGAGGCGTGG GTTCGAATCCCACTTCTGACA146 Leu_TAA_chr6: 1447684-144537766 (+)ACCAGGATGGCCGAGTGGTTAAGGCGTTGGA CTTAAGATCCAATGGACATATGTCCGCGTGG GTTCGAACCCCACTCCTGGTA147 Leu_TAA_chr6:276898-27688980 (-)ACCGGGATGGCCGAGTGGTTAAGGCGTTGGA CTTAAGATCCAATGGGCTGGTGCCCGCGTGG GTTCGAACCCCACTCTCGGTA148 LeuTAAchrl 1:599228-59319310(+)ACCAGAATGGCCGAGTGGTTAAGGCGTTGGA CTTAAGATCCAATGGATTCATATCCGCGTGG GTTCGAACCCCACTTCTGGTA 149 Leu_TAA_chr6:271334-27198416 (-)ACCGGGATGGCTGAGTGGTTAAGGCGTTGGA CTTAAGATCCAATGGACAGGTGTCCGCGTGG GTTCGAGCCCCACTCCCGGTA150 Leu_TAG_chrl7:80632-8023713 (-)GGTAGCGTGGCCGAGCGGTCTAAGGCGCTGG ATTTAGGCTCCAGTCTCTTCGGAGGCGTGGG TTCGAATCCCACCGCTGCCA151 Leu_TAG_chrl4:213529-21093610 (+)GGTAGTGTGGCCGAGCGGTCTAAGGCGCTGG ATTTAGGCTCCAGTCTCTTCGGGGGCGTGGG TTCGAATCCCACCACTGCCA152 Leu_TAG_chrl6:227032-22207113 (-)GGTAGCGTGGCCGAGTGGTCTAAGGCGCTGG ATTTAGGCTCCAGTCATTTCGATGGCGTGGGT TCGAATCCCACCGCTGCCA153 Lys_CTT_chrl4:586613-58706685 (-)GCCCGGCTAGCTCAGTCGGTAGAGCATGGGA CTCTTAATCCCAGGGTCGTGGGTTCGAGCCC CACGTTGGGCG154 Lys_CTT_chrl9:366750-36066822 (+)GCCCAGCTAGCTCAGTCGGTAGAGCATAAGA CTCTTAATCTCAGGGTTGTGGATTCGTGCCCC ATGCTGGGTG WO 2024/216206 PCT/US2024/024492 155 Lys_CTT_chrl9:525393-52425466 (-)GCAGCTAGCTCAGTCGGTAGAGCATGAGACT CTTAATCTCAGGGTCATGGGTTCGTGCCCCAT GTTGGGTGCCA 156 LysCTTchrl: 145395522-145395594 (-)GCCCGGCTAGCTCAGTCGGTAGAGCATGAGA CTCTTAATCTCAGGGTCGTGGGTTCGAGCCCC ACGTTGGGCG157 Lys_CTT_chrl 6:32406-3207478 (-)GCCCGGCTAGCTCAGTCGGTAGAGCATGAGA CCCTTAATCTCAGGGTCGTGGGTTCGAGCCC CACGTTGGGCG158 Lys_CTT_chrl6:32501-3241573 (+)GCCCGGCTAGCTCAGTCGGTAGAGCATGGGA CTCTTAATCTCAGGGTCGTGGGTTCGAGCCCC ACGTTGGGCG159 Lys_CTT_chrl6:32555-3230627 (-)GCCCGGCTAGCTCAGTCGATAGAGCATGAGA CTCTTAATCTCAGGGTCGTGGGTTCGAGCCG CACGTTGGGCG160 Lys_CTT_chrl :554542-55423614 (-)GCCCAGCTAGCTCAGTCGGTAGAGCATGAGA CTCTTAATCTCAGGGTCATGGGTTTGAGCCCC ACGTTTGGTG161 Lys_CTT_chrl6:32939-3215011 (+)GCCTGGCTAGCTCAGTCGGCAAAGCATGAGA CTCTTAATCTCAGGGTCGTGGGCTCGAGCTCC ATGTTGGGCG162 Lys_CTT_chr5:261539-26198611 (-)GCCCGACTACCTCAGTCGGTGGAGCATGGGA CTCTTCATCCCAGGGTTGTGGGTTCGAGCCCC ACATTGGGCA163 Lys_TTT_chrl6:732216-73512288 (-)GCCTGGATAGCTCAGTTGGTAGAGCATCAGA CTTTTAATCTGAGGGTCCAGGGTTCAAGTCCC TGTTCAGGCA164 Lys_TTT_chrl2:273306-27843378 (+)ACCCAGATAGCTCAGTCAGTAGAGCATCAGA CTTTTAATCTGAGGGTCCAAGGTTCATGTCCC TTTTTGGGTG165 Lys_TTT_chrl 1:122430655-122430727 (+)GCCTGGATAGCTCAGTTGGTAGAGCATCAGA CTTTTAATCTGAGGGTCCAGGGTTCAAGTCCC TGTTCAGGCG166 Lys_TTT_chrl :2045655-204475727 (+)GCCCGGATAGCTCAGTCGGTAGAGCATCAGA CTTTTAATCTGAGGGTCCAGGGTTCAAGTCCC TGTTCGGGCG167 Lys_TTT_chr6;275593-27559665 (-)GCCTGGATAGCTCAGTCGGTAGAGCATCAGA CTTTTAATCTGAGGGTCCAGGGTTCAAGTCCC TGTTCAGGCG WO 2024/216206 PCT/US2024/024492 168 LysTTTchrl 1:59323902-59323974 (+)GCCCGGATAGCTCAGTCGGTAGAGCATCAGA CTTTTAATCTGAGGGTCCGGGGTTCAAGTCCC TGTTCGGGCG169 Lys_TTT_chr6:273769-27302841 (-)GCCTGGGTAGCTCAGTCGGTAGAGCATCAGA CTTTTAATCTGAGGGTCCAGGGTTCAAGTCCC TGTCCAGGCG170 Lys_TTT_chr6:287521-28715593 (+)GCCTGGATAGCTCAGTTGGTAGAACATCAGA CTTTTAATCTGACGGTGCAGGGTTCAAGTCCC TGTTCAGGCG 171 Met_CAT_chr8: 1249470-124169542 (-)GCCTCGTTAGCGCAGTAGGTAGCGCGTCAGT CTCATAATCTGAAGGTCGTGAGTTCGATCCTC ACACGGGGCA172 Met_CAT_chrl6:710396-71460468 (+)GCCCTCTTAGCGCAGTGGGCAGCGCGTCAGT CTCATAATCTGAAGGTCCTGAGTTCGAGCCT CAGAGAGGGCA173 Met_CAT_chr6:289352-28912424 (+)GCCTCCTTAGCGCAGTAGGCAGCGCGTCAGT CTCATAATCTGAAGGTCCTGAGTTCGAACCT CAGAGGGGGCA174 Met_CAT_chr6:267574-26735646 (-)GCCCTCTTAGCGCAGCGGGCAGCGCGTCAGT CTCATAATCTGAAGGTCCTGAGTTCGAGCCT CAGAGAGGGCA175 Met_CAT_chr6:267712-26701784 (+)GCCCTCTTAGCGCAGCTGGCAGCGCGTCAGT CTCATAATCTGAAGGTCCTGAGTTCAAGCCT CAGAGAGGGCA176 Met_CAT_chrl6:877628-87417700 (-)GCCTCGTTAGCGCAGTAGGCAGCGCGTCAGT CTCATAATCTGAAGGTCGTGAGTTCGAGCCT CACACGGGGCA177 Met_CAT_chr6:581492-58168564 (-)GCCCTCTTAGTGCAGCTGGCAGCGCGTCAGT TTCATAATCTGAAAGTCCTGAGTTCAAGCCTC AGAGAGGGCA178 Phe_GAA_chr6:287499-28758571 (-)GCCGAAATAGCTCAGTTGGGAGAGCGTTAGA CTGAAGATCTAAAGGTCCCTGGTTCGATCCC GGGTTTCGGCA179 PheGAAchrl 1:59333853-59333925 (-)GCCGAAATAGCTCAGTTGGGAGAGCGTTAGA CTGAAGATCTAAAGGTCCCTGGTTCAATCCC GGGTTTCGGCA WO 2024/216206 PCT/US2024/024492 180 Phe_GAA_chr6:287610-28775682 (-)GCCGAGATAGCTCAGTTGGGAGAGCGTTAGA CTGAAGATCTAAAGGTCCCTGGTTCAATCCC GGGTTTCGGCA181 Phe_GAA_chr6:287093-28791166 (-)GCCGAAATAGCTCAGTTGGGAGAGCGTTAGA CCGAAGATCTTAAAGGTCCCTGGTTCAATCC CGGGTTTCGGCA182 Phe_GAA_chr6:287374-28731447 (-)GCTGAAATAGCTCAGTTGGGAGAGCGTTAGA CTGAAGATCTTAAAGTTCCCTGGTTCAACCCTGGGTTTCAGCC183 ProAGGchr 16:3241989-3242060 (+)GGCTCGTTGGTCTAGGGGTATGATTCTCGCTT AGGATGCGAGAGGTCCCGGGTTCAAATCCCG GACGAGCCC184 ProAGGchrl: 167684725-167684796 (-)GGCTCGTTGGTCTAGGGGTATGATTCTCGCTT AGGGTGCGAGAGGTCCCGGGTTCAAATCCCG GACGAGCCC185 ProCGGchrl: 1673962-167684033 (+)GGCTCGTTGGTCTAGGGGTATGATTCTCGCTT CGGGTGCGAGAGGTCCCGGGTTCAAATCCCG GACGAGCCC186 Pro_CGG_chr6:270521-27059592 (+)GGCTCGTTGGTCTAGGGGTATGATTCTCGCTT CGGGTGTGAGAGGTCCCGGGTTCAAATCCCG GACGAGCCC187 Pro_TGG_chrl4:211165-21101236(+)GGCTCGTTGGTCTAGTGGTATGATTCTCGCTT TGGGTGCGAGAGGTCCCGGGTTCAAATCCCG GACGAGCCC188 ProTGGchrl 1:75946869-75946940 (-)GGCTCGTTGGTCTAGGGGTATGATTCTCGGTT TGGGTCCGAGAGGTCCCGGGTTCAAATCCCG GACGAGCCC189 Pro_TGG_chr5: 1805854-180615925 (-)GGCTCGTTGGTCTAGGGGTATGATTCTCGCTT TGGGTGCGAGAGGTCCCGGGTTCAAATCCCG GACGAGCCC190 SeC_TCA_chrl9:451859-45981945 (-)GCCCGGATGATCCTCAGTGGTCTGGGGTGCA GGCTTCAAACCTGTAGCTGTCTAGCGACAGA GTGGTTCAATTCCACCTTTCGGGCG191 SeC_TCA_chr22:446537-44546620 (+)GCTCGGATGATCCTCAGTGGTCTGGGGTGCA GGCTTCAAACCTGTAGCTGTCTAGTGACAGA GTGGTTCAATTCCACCTTTGTA WO 2024/216206 PCT/US2024/024492 192 Ser_AGA_chr6:275554-27509635 (-)GTAGTCGTGGCCGAGTGGTTAAGGCGATGGACTAGAAATCCATTGGGGTTTCCCCGCGCAGG TTCGAATCCTGCCGACTACG193 Ser_AGA_chr6:263817-26327898 (+)GTAGTCGTGGCCGAGTGGTTAAGGCGATGGA CTAGAAATCCATTGGGGTCTCCCCGCGCAGG TTCGAATCCTGCCGACTACG194 Ser_AGA_chr6:274987-27500068 (+)GTAGTCGTGGCCGAGTGGTTAAGGCGATGGA CTAGAAATCCATTGGGGTTTCCCCACGCAGG TTCGAATCCTGCCGACTACG195 Ser_AGA_chr6;275192-27521273 (-)GTAGTCGTGGCCGAGTGGTTAAGGTGATGGA CTAGAAACCCATTGGGGTCTCCCCGCGCAGG TTCGAATCCTGCCGACTACG196 Ser_CGA_chrl7:80199-8042280 (-)GCTGTGATGGCCGAGTGGTTAAGGCGTTGGA CTCGAAATCCAATGGGGTCTCCCCGCGCAGG TTCGAATCCTGCTCACAGCG197 Ser_CGA_chr6:271628-27177709 (+)GCTGTGATGGCCGAGTGGTTAAGGCGTTGGA CTCGAAATCCAATGGGGTCTCCCCGCGCAGG TTCAAATCCTGCTCACAGCG198 S er_C GA_chr6 ;276229-27640310 (-)GCTGTGATGGCCGAGTGGTTAAGGTGTTGGA CTCGAAATCCAATGGGGGTTCCCCGCGCAGG TTCAAATCCTGCTCACAGCG199 Ser_CGA_chrl2:564148-56584229(+)GTCACGGTGGCCGAGTGGTTAAGGCGTTGGA CTCGAAATCCAATGGGGTTTCCCCGCACAGG TTCGAATCCTGTTCGTGACG200 Ser_GCT_chr6:270085-27065166 (+)GACGAGGTGGCCGAGTGGTTAAGGCGATGG ACTGCTAATCCATTGTGCTCTGCACGCGTGG GTTCGAATCCCACCCTCGTCG201 Ser_GCT_chr6:272775-27265856 (+)GACGAGGTGGCCGAGTGGTTAAGGCGATGG ACTGCTAATCCATTGTGCTCTGCACGCGTGG GTTCGAATCCCACCTTCGTCG202 SerGCTchrl 1:66115591-66115672 (+)GACGAGGTGGCCGAGTGGTTAAGGCGATGG ACTGCTAATCCATTGTGCTTTGCACGCGTGGG TTCGAATCCCATCCTCGTCG203 Ser_GCT_chr6:285117-28565198 (-)GACGAGGTGGCCGAGTGGTTAAGGCGATGG ACTGCTAATCCATTGTGCTCTGCACGCGTGG GTTCGAATCCCATCCTCGTCG204 Ser_GCT_chr6:281815-28180896 (+)GACGAGGTGGCCGAGTGGTTAAGGCGATGG ACTGCTAATCCATTGTGCTCTGCACACGTGG GTTCGAATCCCATCCTCGTCG WO 2024/216206 PCT/US2024/024492 205 Ser_GCT_chr6:263718-26305801 (-)GGAGAGGCCTGGCCGAGTGGTTAAGGCGATG GACTGCTAATCCATTGTGCTCTGCACGCGTG GGTTCGAATCCCATCCTCGTCG206 Ser_TGA_chrlO:694261-69524342 (+)GCAGCGATGGCCGAGTGGTTAAGGCGTTGGA CTTGAAATCCAATGGGGTCTCCCCGCGCAGG TTCGAACCCTGCTCGCTGCG207 Ser_TGA_chr6;275468-27513549 (+)GTAGTCGTGGCCGAGTGGTTAAGGCGATGGA CTTGAAATCCATTGGGGTTTCCCCGCGCAGG TTCGAATCCTGCCGACTACG208 Ser_TGA_chr6:263824-26312905 (-)GTAGTCGTGGCCGAGTGGTTAAGGCGATGGA CTTGAAATCCATTGGGGTCTCCCCGCGCAGG TTCGAATCCTGCCGACTACG209 Ser_TGA_chr6;274607-27473688 (-)GTAGTCGTGGCCGAGTGGTTAAGGCGATGGA CTTGAAATCCATTGGGGTTTCCCCGCGCAGG TTCGAATCCTGTCGGCTACG210 Thr_AGT_chrl7:80478-8090551 (+)GGCGCCGTGGCTTAGTTGGTTAAAGCGCCTG TCTAGTAAACAGGAGATCCTGGGTTCGAATC CCAGCGGTGCCT211 Thr_AGT_chr6:265145-26533218 (-)GGCTCCGTGGCTTAGCTGGTTAAAGCGCCTG TCTAGTAAACAGGAGATCCTGGGTTCGAATC CCAGCGGGGCCT212 Thr_AGT_chr6:286795-28693868 (+)GGCTCCGTAGCTTAGTTGGTTAAAGCGCCTG TCTAGTAAACAGGAGATCCTGGGTTCGACTC CCAGCGGGGCCT213 Thr_AGT_chr6 ;276473-27694546 (+)GGCTTCGTGGCTTAGCTGGTTAAAGCGCCTG TCTAGTAAACAGGAGATCCTGGGTTCGAATC CCAGCGAGGCCT214 Thr_AGT_chrl7;80770-8042843 (-)GGCGCCGTGGCTTAGCTGGTTAAAGCGCCTG TCTAGTAAACAGGAGATCCTGGGTTCGAATC CCAGCGGTGCCT215 Thr AGT chr6:271050-27130123 (+)GGCCCTGTGGCTTAGCTGGTCAAAGCGCCTG TCTAGTAAACAGGAGATCCTGGGTTCGAATC CCAGCGGGGCCT216 Thr_CGT_chr6:284770-28456843 (-)GGCTCTATGGCTTAGTTGGTTAAAGCGCCTGT CTCGTAAACAGGAGATCCTGGGTTCGACTCC CAGTGGGGCCT217 Thr_CGT_chrl6:149750-14379821 (+)GGCGCGGTGGCCAAGTGGTAAGGCGTCGGTC TCGTAAACCGAAGATCACGGGTTCGAACCCC GTCCGTGCCT WO 2024/216206 PCT/US2024/024492 218 Thr_CGT_chr6:286984-28616057 (-)GGCTCTGTGGCTTAGTTGGCTAAAGCGCCTG TCTCGTAAACAGGAGATCCTGGGTTCGAATC CCAGCGGGGCCT219 Thr_CGT_chrl 7:297093-29877164 (+)GGCGCGGTGGCCAAGTGGTAAGGCGTCGGTC TCGTAAACCGAAGATCGCGGGTTCGAACCCC GTCCGTGCCT220 Thr_CGT_chr6;275135-27586208 (+)GGCCCTGTAGCTCAGCGGTTGGAGCGCTGGT CTCGTAAACCTAGGGGTCGTGAGTTCAAATC TCACCAGGGCCT221 Thr_TGT_chr6 :284329-28442402 (-)GGCTCTATGGCTTAGTTGGTTAAAGCGCCTGT CTTGTAAACAGGAGATCCTGGGTTCGAATCC CAGTAGAGCCT222 ThrTGTchrl :222638347-222638419 (+)GGCTCCATAGCTCAGTGGTTAGAGCACTGGT CTTGTAAACCAGGGGTCGCGAGTTCGATCCT CGCTGGGGCCT223 Thr_TGT_chrl4:211949-21082021 (-)GGCTCCATAGCTCAGGGGTTAGAGCGCTGGT CTTGTAAACCAGGGGTCGCGAGTTCAATTCT CGCTGGGGCCT224 Thr_TGT_chrl4:219319-21099391 (-)GGCTCCATAGCTCAGGGGTTAGAGCACTGGT CTTGTAAACCAGGGGTCGCGAGTTCAAATCT CGCTGGGGCCT225 Thr_TGT_chrl4:21 9849-21149921 (+)GGCCCTATAGCTCAGGGGTTAGAGCACTGGT CTTGTAAACCAGGGGTCGCGAGTTCAAATCT CGCTGGGGCCT226 Thr_TGT_chr5: 1808687-180618758 (-)GGCTCCATAGCTCAGGGGTTAGAGCACTGGT CTTGTAAACCAGGGTCGCGAGTTCAAATCTC GCTGGGGCCT227 Trp_CCA_chrl7:81187-8124258 (-)GGCCTCGTGGCGCAACGGTAGCGCGTCTGAC TCCAGATCAGAAGGTTGCGTGTTCAAATCAC GTCGGGGTCA228 Trp CCA chrl7:191494-19411565 (+)GACCTCGTGGCGCAATGGTAGCGCGTCTGAC TCCAGATCAGAAGGTTGCGTGTTCAAGTCAC GTCGGGGTCA229 Trp_CCA_chr6:263330-26319401 (-)GACCTCGTGGCGCAACGGTAGCGCGTCTGAC TCCAGATCAGAAGGTTGCGTGTTCAAATCAC GTCGGGGTCA230 Trp_CCA_chrl2:988030-98898101 (+)GACCTCGTGGCGCAACGGTAGCGCGTCTGAC TCCAGATCAGAAGGCTGCGTGTTCGAATCAC GTCGGGGTCA WO 2024/216206 PCT/US2024/024492 231 Trp_CCA_chr7: 990307-99067378(+)GACCTCGTGGCGCAACGGCAGCGCGTCTGAC TCCAGATCAGAAGGTTGCGTGTTCAAATCAC GTCGGGGTCA232 Tyr_ATA_chr2:2191 0549-219110641 (+)CCTTCAATAGTTCAGCTGGTAGAGCAGAGGA CTATAGCTACTTCCTCAGTAGGAGACGTCCTT AGGTTGCTGGTTCGATTCCAGCTTGAAGGA 233 Tyr_GTA_chr6:265086-26569176 (+)CCTTCGATAGCTCAGTTGGTAGAGCGGAGGA CTGTAGTTGGCTGTGTCCTTAGACATCCTTAG GTCGCTGGTTCGAATCCGGCTCGAAGGA234 Tyr_GTA_chr2;272650-27273738 (+)CCTTCGATAGCTCAGTTGGTAGAGCGGAGGA CTGTAGTGGATAGGGCGTGGCAATCCTTAGG TCGCTGGTTCGATTCCGGCTCGAAGGA235 Tyr_GTA_chr6:265332-26577420 (+)CCTTCGATAGCTCAGTTGGTAGAGCGGAGGA CTGTAGGCTCATTAAGCAAGGTATCCTTAGG TCGCTGGTTCGAATCCGGCTCGGAGGA236 Tyr_GTA_chrl4:21 5623-21125716(-)CCTTCGATAGCTCAGCTGGTAGAGCGGAGGA CTGTAGATTGTATAGACATTTGCGGACATCCT TAGGTCGCTGGTTCGATTCCAGCTCGAAGGA 237 Tyr_GTA_chr8 :670602-67025694 (+)CCTTCGATAGCTCAGCTGGTAGAGCGGAGGA CTGTAGCTACTTCCTCAGCAGGAGACATCCTT AGGTCGCTGGTTCGATTCCGGCTCGAAGGA238 Tyr_GTA_chr8: 670223-67026311 (+)CCTTCGATAGCTCAGCTGGTAGAGCGGAGGA CTGTAGGCGCGCGCCCGTGGCCATCCTTAGG TCGCTGGTTCGATTCCGGCTCGAAGGA239 Tyr_GTA_chrl4:211258-21121351 (-)CCTTCGATAGCTCAGCTGGTAGAGCGGAGGA CTGTAGCCTGTAGAAACATTTGTGGACATCC TTAGGTCGCTGGTTCGATTCCGGCTCGAAGG A240 Tyr_GTA_chrl4:211351-21131444 (-)CCTTCGATAGCTCAGCTGGTAGAGCGGAGGA CTGTAGATTGTACAGACATTTGCGGACATCC TTAGGTCGCTGGTTCGATTCCGGCTCGAAGG A241 Tyr_GTA_chrl4:21 1432-21151520(+)CCTTCGATAGCTCAGCTGGTAGAGCGGAGGA CTGTAGTACTTAATGTGTGGTCATCCTTAGGT CGCTGGTTCGATTCCGGCTCGAAGGA242 Tyr_GTA_chr6 ;265102-26595190 (+)CCTTCGATAGCTCAGCTGGTAGAGCGGAGGA CTGTAGGGGTTTGAATGTGGTCATCCTTAGGT CGCTGGTTCGAATCCGGCTCGGAGGA WO 2024/216206 PCT/US2024/024492 243 Tyr_GTA_chrl4:21 8117-21128210(-)CCTTCGATAGCTCAGCTGGTAGAGCGGAGGA CTGTAGACTGCGGAAACGTTTGTGGACATCC TTAGGTCGCTGGTTCAATTCCGGCTCGAAGG A244 Tyr_GTA_chr6:265798-26575887 (+)CTTTCGATAGCTCAGTTGGTAGAGCGGAGGA CTGTAGGTTCATTAAACTAAGGCATCCTTAG GTCGCTGGTTCGAATCCGGCTCGAAGGA245 Tyr_GTA_chr8 :666532-66609619 (-)TCTTCAATAGCTCAGCTGGTAGAGCGGAGGA CTGTAGGTGCACGCCCGTGGCCATTCTTAGG TGCTGGTTTGATTCCGACTTGGAGAG246 Val_AAC_chr3: 1690018-169490090 (+)GTTTCCGTAGTGTAGTGGTTATCACGTTCGCC TAACACGCGAAAGGTCCCCGGTTCGAAACCG GGCGGAAACA247 Val_AAC_chr5: 1805416-180615488 (-)GTTTCCGTAGTGTAGTGGTCATCACGTTCGCC TAACACGCGAAAGGTCCCCGGTTCGAAACCG GGCGGAAACA248 Val_AAC_chr6:2761 707-27618779 (-)GTTTCCGTAGTGTAGTGGTTATCACGTTCGCC TAACACGCGAAAGGTCCCTGGATCAAAACCA GGCGGAAACA249 Val_AAC_chr6 :276885-27648957 (-)GTTTCCGTAGTGTAGTGGTTATCACGTTCGCC TAACACGCGAAAGGTCCGCGGTTCGAAACCG GGCGGAAACA250 Val_AAC_chr6 :272288-27203360 (+)GTTTCCGTAGTGTAGTGGTTATCACGTTTGCC TAACACGCGAAAGGTCCCCGGTTCGAAACCG GGCAGAAACA251 Val_AAC_chr6:287206-28703277 (-)GGGGGTGTAGCTCAGTGGTAGAGCGTATGCT TAACATTCATGAGGCTCTGGGTTCGATCCCC AGCACTTCCA252 ValCACchrl: 161369490-161369562 (-)GTTTCCGTAGTGTAGTGGTTATCACGTTCGCC TCACACGCGAAAGGTCCCCGGTTCGAAACCG GGCGGAAACA253 Val_CAC_chr6:272049-27248121 (-)GCTTCTGTAGTGTAGTGGTTATCACGTTCGCC TCACACGCGAAAGGTCCCCGGTTCGAAACCG GGCAGAAGCA254 Val_CAC_chrl9:47647-4724719 (-)GTTTCCGTAGTGTAGCGGTTATCACATTCGCC TCACACGCGAAAGGTCCCCGGTTCGATCCCG GGCGGAAACA WO 2024/216206 PCT/US2024/024492 255 Val_CAC_chrl: 1498555-149298627 (-)GTTTCCGTAGTGTAGTGGTTATCACGTTCGCC TCACACGCGAAAGGTCCCCGGTTCGAAACTG GGCGGAAACA256 Val_CAC_chrl: 149684088-149684161 (-)GTTTCCGTAGTGTAGTGGTTATCACGTTCGCC TCACACGCGTAAAGGTCCCCGGTTCGAAACC GGGCGGAAACA257 Val_CAC_chr6;271867-27173939 (-)GTTTCCGTAGTGGAGTGGTTATCACGTTCGCC TCACACGCGAAAGGTCCCCGGTTTGAAACCA GGCGGAAACA258 ValTACchrl 1:598102-59318174 (-)GGTTCCATAGTGTAGTGGTTATCACGTCTGCT TTACACGCAGAAGGTCCTGGGTTCGAGCCCC AGTGGAACCA259 ValTACchrl 1:59318460-59318532 (-)GGTTCCATAGTGTAGCGGTTATCACGTCTGCT TTACACGCAGAAGGTCCTGGGTTCGAGCCCC AGTGGAACCA260 Val_TAC_chrlO:58674-5895746 (-)GGTTCCATAGTGTAGTGGTTATCACATCTGCT TTACACGCAGAAGGTCCTGGGTTCAAGCCCC AGTGGAACCA261 Val_TAC_chr6:272405-27258477 (+)GTTTCCGTGGTGTAGTGGTTATCACATTCGCC TTACACGCGAAAGGTCCTCGGGTCGAAACCG AGCGGAAACA262 iMet_CAT_chrl:153643726-153643797 (+)AGCAGAGTGGCGCAGCGGAAGCGTGCTGGG CCCATAACCCAGAGGTCGATGGATCGAAACC ATCCTCTGCTA263 iMet_CAT_chr6:275664-27745735 (+)AGCAGAGTGGCGCAGCGGAAGCGTGCTGGG CCCATAACCCAGAGGTCGATGGATCTAAACC ATCCTCTGCTA264 GluTTCchrl: 168773-16861845 (-)TCCCTGGTGGTCTAGTGGCTAGGATTCGGCGCTTTCACCGCCGCGGCCCGGGTTCGATTCCCG GTCAGGGAAT265 GlyCCCchr 1:170765-17004836 (-)GCGTTGGTGGTTTAGTGGTAGAATTCTCGCCT CCCATGCGGGAGACCCGGGTTCAATTCCCGG CCACTGCAC266 Gly_CCC_chrl :170779-17053850 (+)GGCCTTGGTGGTGCAGTGGTAGAATTCTCGC CTCCCACGTGGGAGACCCGGGTTCAATTCCC GGCCAATGCA267 GluTTCchrl: 171077-17199149 (+)GTCCCTGGTGGTCTAGTGGCTAGGATTCGGCGCTTTCACCGCCGCGGCCCGGGTTCGATTCCC GGCCAGGGAA WO 2024/216206 PCT/US2024/024492 268 Asn_GTT_chrl:17216171-17216245 (+)TGTCTCTGTGGCGCAATCGGTTAGCGCGTTCG GCTGTTAACCGAAAGATTGGTGGTTCGAGCC CACCCAGGGACG269 Arg_TCT_chrl:94313128-94313213 (+)TGGCTCCGTGGCGCAATGGATAGCGCATTGG ACTTCTAGAGGCTGAAGGCATTCAAAGGTTC CGGGTTCGAGTCCCGGCGGAGTCG 270 LysCTTchrl: 145395521-145395594 (-)GCCCGGCTAGCTCAGTCGGTAGAGCATGAGA CTCTTAATCTCAGGGTCGTGGGTTCGAGCCCCACGTTGGGCGC271 HisGTGchrl: 145396880-145396952 (-)GCCGTGATCGTATAGTGGTTAGTACTCTGCGT TGTGGCCGCAGCAACCTCGGTTCGAATCCGA GTCACGGCAG272 GlyTCCchrl: 1457863-145397935 (-)GCGTTGGTGGTATAGTGGTGAGCATAGCTGC CTTCCAAGCAGTTGACCCGGGTTCGATTCCC GGCCAACGCAG273 GluCTCchrl: 145399232-145399304 (-)TCCCTGGTGGTCTAGTGGTTAGGATTCGGCGCTCTCACCGCCGCGGCCCGGGTTCGATTCCC GGTCAGGGAAA274 GlnCTGchrl: 145963303-145963375 (+)AGGTTCCATGGTGTAATGGTGAGCACTCTGG ACTCTGAATCCAGCGATCCGAGTTCGAGTCT CGGTGGAACCT275 AsnGTTchrl: 148000804-148000878 (+)TGTCTCTGTGGCGTAGTCGGTTAGCGCGTTCGGCTGTTAACCGAAAAGTTGGTGGTTCGAGCC CACCCAGGAACG276 AsnGTTchrl: 1488114-148248188 (+)TGTCTCTGTGGCGCAATCGGTTAGCGCGTTCG GCTGTTAACCGAAAGGTTGGTGGTTCGAGCC CACCCAGGGACG277 AsnGTTchrl: 1488313-148598387 (-)GTCTCTGTGGCGCAATCGGTTAGCGCATTCG GCTGTTAACCGAAAGGTTGGTGGTTCGAGCC CACCCAGGGACGC278 AsnGTTchrl: 1490569-149230643 (-)GTCTCTGTGGCGCAATGGGTTAGCGCGTTCGGCTGTTAACCGAAAGGTTGGTGGTTCGAGCC CATCCAGGGACGC279 Val_CAC_chrl: 149294665-149294736 (-)GCACTGGTGGTTCAGTGGTAGAATTCTCGCC TCACACGCGGGACACCCGGGTTCAATTCCCG GTCAAGGCAA WO 2024/216206 PCT/US2024/024492 280 Val_CAC_chrl: 149298554-149298627 (-)GTTTCCGTAGTGTAGTGGTTATCACGTTCGCC TCACACGCGAAAGGTCCCCGGTTCGAAACTG GGCGGAAACAG281 GlyCCCchrl: 149680209-149680280 (-)GCACTGGTGGTTCAGTGGTAGAATTCTCGCC TCCCACGCGGGAGACCCGGGTTTAATTCCCG GTCAAGATAA282 Val_CAC_chrl: 149684087-149684161 (-)GTTTCCGTAGTGTAGTGGTTATCACGTTCGCC TCACACGCGTAAAGGTCCCCGGTTCGAAACC GGGCGGAAACAT283 Met_CAT_chrl: 153643725-153643797 (+)TAGCAGAGTGGCGCAGCGGAAGCGTGCTGGGCCCATAACCCAGAGGTCGATGGATCGAAAC CATCCTCTGCTA284 ValCACchrl: 161369489-161369562 (-)GTTTCCGTAGTGTAGTGGTTATCACGTTCGCC TCACACGCGAAAGGTCCCCGGTTCGAAACCG GGCGGAAACAA285 AspGTCchrl: 161410614-161410686 (-)TCCTCGTTAGTATAGTGGTGAGTATCCCCGCC TGTCACGCGGGAGACCGGGGTTCGATTCCCC GACGGGGAGG286 GlyGCCchrl: 1613093-161413164 (+)TGCATGGGTGGTTCAGTGGTAGAATTCTCGC CTGCCACGCGGGAGGCCCGGGTTCGATTCCC GGCCCATGCA287 Glu_CTC_chrl:161417017-161417089 (-)TCCCTGGTGGTCTAGTGGTTAGGATTCGGCGCTCTCACCGCCGCGGCCCGGGTTCGATTCCC GGTCAGGGAAG288 AspGTCchrl: 1612934-161493006 (+)ATCCTTGTTACTATAGTGGTGAGTATCTCTGC CTGTCATGCGTGAGAGAGGGGGTCGATTCCC CGACGGGGAG289 GlyGCCchrl :1613636-161493707 (-)GCATTGGTGGTTCAGTGGTAGAATTCTCGCCT GCCACGCGGGAGGCCCGGGTTCGATTCCCGG CCAATGCAC290 Leu CAG chrl:1610131-161500214 (-)GTCAGGATGGCCGAGCGGTCTAAGGCGCTGC GTTCAGGTCGCAGTCTCCCCTGGAGGCGTGG GTTCGAATCCCACTCCTGACAA291 Gly_TCC_chrl: 161500902-161500974 (+)CGCGTTGGTGGTATAGTGGTGAGCATAGCTG CCTTCCAAGCAGTTGACCCGGGTTCGATTCCC GGCCAACGCA292 Asn_GTT_chrl:161510030-161510104 (+)CGTCTCTGTGGCGCAATCGGTTAGCGCGTTC GGCTGTTAACCGAAAGGTTGGTGGTTCGATC CCACCCAGGGACG WO 2024/216206 PCT/US2024/024492 293 GluTTCchrl: 1612507-161582579 (+)CGCGTTGGTGGTGTAGTGGTGAGCACAGCTG CCTTTCAAGCAGTTAACGCGGGTTCGATTCCC GGGTAACGAA294 ProCGGchrl: 167683961-167684033 (+)CGGCTCGTTGGTCTAGGGGTATGATTCTCGCT TCGGGTGCGAGAGGTCCCGGGTTCAAATCCC GGACGAGCCC295 ProAGGchrl: 167684724-167684796 (-)GGCTCGTTGGTCTAGGGGTATGATTCTCGCTT AGGGTGCGAGAGGTCCCGGGTTCAAATCCCG GACGAGCCCT296 Lys_TTT_chrl :2045654-204475727 (+)CGCCCGGATAGCTCAGTCGGTAGAGCATCAG ACTTTTAATCTGAGGGTCCAGGGTTCAAGTC CCTGTTCGGGCG297 Lys_TTT_chrl :2046157-204476230 (-)GCCCGGATAGCTCAGTCGGTAGAGCATCAGA CTTTTAATCTGAGGGTCCAGGGTTCAAGTCCC TGTTCGGGCGT298 Leu_CAA_chrl :2498053-249168159 (+)TGTCAGGATGGCCGAGTGGTCTAAGGCGCCA GACTCAAGGTAAGCACCTTGCCTGCGGGCTT TCTGGTCTCCGGATGGAGGCGTGGGTTCGAA TCCCACTTCTGACA299 GluCTCchrl :2498446-249168518 (+)TTCCCTGGTGGTCTAGTGGTTAGGATTCGGCG CTCTCACCGCCGCGGCCCGGGTTCGATTCCC GGTCAGGAAA300 Tyr_GTA_chr2:272649-27273738 (+)GCCTTCGATAGCTCAGTTGGTAGAGCGGAGG ACTGTAGTGGATAGGGCGTGGCAATCCTTAG GTCGCTGGTTCGATTCCGGCTCGAAGGA301 Ala_AGC_chr2 :272081-27274154 (+)CGGGGGATTAGCTCAAATGGTAGAGCGCTCG CTTAGCATGCGAGAGGTAGCGGGATCGATGC CCGCATCCTCCA302 Ile_TAT_chr2:430375-43037768 (+)AGCTCCAGTGGCGCAATCGGTTAGCGCGCGG TACTTATACAGCAGTACATGCAGAGCAATGC CGAGGTTGTGAGTTCGAGCCTCACCTGGAGC A303 Gly_CCC_chr2 :704122-70476193 (-)GCGCCGCTGGTGTAGTGGTATCATGCAAGAT TCCCATTCTTGCGACCCGGGTTCGATTCCCGGGCGGCGCAT304 Glu_TTC_chr2:1314700-131094772 (-)TCCCATATGGTCTAGCGGTTAGGATTCCTGGT TTTCACCCAGGTGGCCCGGGTTCGACTCCCG GTATGGGAAC WO 2024/216206 PCT/US2024/024492 305 Ala_CGC_chr2: 1577280-157257352 (+)GGGGGATGTAGCTCAGTGGTAGAGCGCGCGC TTCGCATGTGTGAGGTCCCGGGTTCAATCCCC GGCATCTCCA306 Gly_GCC_chr2: 1577658-157257729 (-)GCATTGGTGGTTCAGTGGTAGAATTCTCGCCT GCCACGCGGGAGGCCCGGGTTCGATTCCCGG CCAATGCAA307 Arg_ACG_chr3 :457490-45730563 (-)GGGCCAGTGGCGCAATGGATAACGCGTCTGA CTACGGATCAGAAGATTCTAGGTTCGACTCC TGGCTGGCTCGC308 Val_AAC_chr3: 1690017-169490090 (+)GGTTTCCGTAGTGTAGTGGTTATCACGTTCGC CTAACACGCGAAAGGTCCCCGGTTCGAAACC GGGCGGAAACA309 Val_AAC_chr5:1806609-180596682 (+)AGTTTCCGTAGTGTAGTGGTTATCACGTTCGC CTAACACGCGAAAGGTCCCCGGTTCGAAACC GGGCGGAAACA310 Leu_AAG_chr5 :1814700-180614782 (+)AGGTAGCGTGGCCGAGCGGTCTAAGGCGCTG GATTAAGGCTCCAGTCTCTTCGGGGGCGTGG GTTCGAATCCCACCGCTGCCA311 Val_AAC_chr5: 1805415-180615488 (-)GTTTCCGTAGTGTAGTGGTCATCACGTTCGCC TAACACGCGAAAGGTCCCCGGTTCGAAACCG GGCGGAAACAT312 Pro_TGG_chr5: 1805853-180615925 (-)GGCTCGTTGGTCTAGGGGTATGATTCTCGCTT TGGGTGCGAGAGGTCCCGGGTTCAAATCCCG GACGAGCCCA313 Thr_TGT_chr5: 1808686-180618758 (-)GGCTCCATAGCTCAGGGGTTAGAGCACTGGT CTTGTAAACCAGGGTCGCGAGTTCAAATCTC GCTGGGGCCTG314 Ala_TGC_chr5: 1803867-180633939 (+)TGGGGATGTAGCTCAGTGGTAGAGCGCATGC TTTGCATGTATGAGGCCCCGGGTTCGATCCCC GGCATCTCCA315 Lys_CTT_chr5: 1804754-180634827 (+)CGCCCGGCTAGCTCAGTCGGTAGAGCATGAG ACTCTTAATCTCAGGGTCGTGGGTTCGAGCC CCACGTTGGGCG316 Val_AAC_chr5: 1805269-180645342 (-)GTTTCCGTAGTGTAGTGGTTATCACGTTCGCC TAACACGCGAAAGGTCCCCGGTTCGAAACCG GGCGGAAACAA317 Lys_CTT_chr5: 1808978-180649051 (-)GCCCGGCTAGCTCAGTCGGTAGAGCATGAGA CTCTTAATCTCAGGGTCGTGGGTTCGAGCCCC ACGTTGGGCGT WO 2024/216206 PCT/US2024/024492 318 Val_CAC_chr5: 1809394-180649467 (-)GTTTCCGTAGTGTAGTGGTTATCACGTTCGCC TCACACGCGAAAGGTCCCCGGTTCGAAACCG GGCGGAAACAC319 Met_CAT_chr6:262753-26286825 (+)CAGCAGAGTGGCGCAGCGGAAGCGTGCTGG GCCCATAACCCAGAGGTCGATGGATCGAAAC CATCCTCTGCTA320 Ser_GCT_chr6:263717-26305801 (-)GGAGAGGCCTGGCCGAGTGGTTAAGGCGATG GACTGCTAATCCATTGTGCTCTGCACGCGTG GGTTCGAATCCCATCCTCGTCGC321 Gln_TTG_chr6:2631 423-26311495 (-)GGCCCCATGGTGTAATGGTTAGCACTCTGGA CTTTGAATCCAGCGATCCGAGTTCAAATCTC GGTGGGACCTG322 Gln_TTG_chr6;263974-26312046 (-)GGCCCCATGGTGTAATGGTTAGCACTCTGGA CTTTGAATCCAGCGATCCGAGTTCAAATCTC GGTGGGACCTA323 Ser_TGA_chr6;263823-26312905 (-)GTAGTCGTGGCCGAGTGGTTAAGGCGATGGA CTTGAAATCCATTGGGGTCTCCCCGCGCAGG TTCGAATCCTGCCGACTACGG 324 Met_CAT_chr6:263351-26313423 (-)AGCAGAGTGGCGCAGCGGAAGCGTGCTGGG CCCATAACCCAGAGGTCGATGGATCGAAACC ATCCTCTGCTAT325 Arg_TCG_chr6:263045-26323118 (+)GGACCACGTGGCCTAATGGATAAGGCGTCTG ACTTCGGATCAGAAGATTGAGGGTTCGAATC CCTCCGTGGTTA326 Ser_AGA_chr6:263816-26327898 (+)TGTAGTCGTGGCCGAGTGGTTAAGGCGATGG ACTAGAAATCCATTGGGGTCTCCCCGCGCAG GTTCGAATCCTGCCGACTACG327 Met_CAT_chr6:263528-26330600 (-)AGCAGAGTGGCGCAGCGGAAGCGTGCTGGG CCCATAACCCAGAGGTCGATGGATCGAAACC ATCCTCTGCTAG328 Leu CAG chr6:265435-26521518 (+)CGTCAGGATGGCCGAGCGGTCTAAGGCGCTG CGTTCAGGTCGCAGTCTCCCCTGGAGGCGTG GGTTCGAATCCCACTCCTGACA329 Thr_AGT_chr6:265144-26533218 (-)GGCTCCGTGGCTTAGCTGGTTAAAGCGCCTG TCTAGTAAACAGGAGATCCTGGGTTCGAATC CCAGCGGGGCCTG330 Arg_ACG_chr6:26537725-26537798 (+)AGGGCCAGTGGCGCAATGGATAACGCGTCTG ACTACGGATCAGAAGATTCCAGGTTCGACTC CTGGCTGGCTCG WO 2024/216206 PCT/US2024/024492 331 Val_CAC_chr6:265281-26538354 (+)GGTTTCCGTAGTGTAGTGGTTATCACGTTCGC CTCACACGCGAAAGGTCCCCGGTTCGAAACC GGGCGGAAACA332 Ala_CGC_chr6:265730-26553802 (+)AGGGGATGTAGCTCAGTGGTAGAGCGCATGC TTCGCATGTATGAGGTCCCGGGTTCGATCCCC GGCATCTCCA333 Ile_AAT_chr6:265549-26554423 (+)TGGCCGGTTAGCTCAGTTGGTTAGAGCGTGG TGCTAATAACGCCAAGGTCGCGGGTTCGATC CCCGTACGGGCCA334 Pro_AGG_chr6:265497-26555569 (+)CGGCTCGTTGGTCTAGGGGTATGATTCTCGCT TAGGGTGCGAGAGGTCCCGGGTTCAAATCCC GGACGAGCCC335 Lys_CTT_chr6;265773-26556846 (+)AGCCCGGCTAGCTCAGTCGGTAGAGCATGAG ACTCTTAATCTCAGGGTCGTGGGTTCGAGCC CCACGTTGGGCG336 Tyr_GTA_chr6 ;265085-26569176 (+)TCCTTCGATAGCTCAGTTGGTAGAGCGGAGG ACTGTAGTTGGCTGTGTCCTTAGACATCCTTA GGTCGCTGGTTCGAATCCGGCTCGAAGGA 337 Ala_AGC_chr6:265091-26572164 (-)GGGGAATTAGCTCAAATGGTAGAGCGCTCGC TTAGCATGCGAGAGGTAGCGGGATCGATGCC CGCATTCTCCAG338 Met_CAT_chr6:267443-26766516 (+)CGCCCTCTTAGCGCAGCGGGCAGCGCGTCAGTCTCATAATCTGAAGGTCCTGAGTTCGAGCCT CAGAGAGGGCA339 Ile_TAT_chr6:269824-26988218 (+)TGCTCCAGTGGCGCAATCGGTTAGCGCGCGG TACTTATATGGCAGTATGTGTGCGAGTGATG CCGAGGTTGTGAGTTCGAGCCTCACCTGGAG CA340 His_GTG_chr6:271905-27125977 (+)TGCCGTGATCGTATAGTGGTTAGTACTCTGCG TTGTGGCCGCAGCAACCTCGGTTCGAATCCG AGTCACGGCA341 Ile_AAT_chr6:271493-27145067 (-)GGCCGGTTAGCTCAGTTGGTTAGAGCGTGGT GCTAATAACGCCAAGGTCGCGGGTTCGATCC CCGTACGGGCCAC342 Val_AAC_chr6: 272287-27203360 (+)AGTTTCCGTAGTGTAGTGGTTATCACGTTTGC CTAACACGCGAAAGGTCCCCGGTTCGAAACC GGGCAGAAACA WO 2024/216206 PCT/US2024/024492 343 Val_CAC_chr6:272048-27248121 (-)GCTTCTGTAGTGTAGTGGTTATCACGTTCGCC TCACACGCGAAAGGTCCCCGGTTCGAAACCG GGCAGAAGCAA344 Asp_GTC_chr6 :274452-27447524 (+)TTCCTCGTTAGTATAGTGGTGAGTATCCCCGC CTGTCACGCGGGAGACCGGGGTTCGATTCCC CGACGGGGAG345 Ser_TGA_chr6:274606-27473688 (-)GTAGTCGTGGCCGAGTGGTTAAGGCGATGGA CTTGAAATCCATTGGGGTTTCCCCGCGCAGG TTCGAATCCTGTCGGCTACGG346 Gln_CTG_chr6:274307-27487379 (+)AGGTTCCATGGTGTAATGGTTAGCACTCTGG ACTCTGAATCCAGCGATCCGAGTTCAAATCT CGGTGGAACCT347 Asp_GTC_chr6:275235-27551307 (-)TCCTCGTTAGTATAGTGGTGAGTGTCCCCGTC TGTCACGCGGGAGACCGGGGTTCGATTCCCC GACGGGGAGA348 Val_AAC_chr6:276706-27618779 (-)GTTTCCGTAGTGTAGTGGTTATCACGTTCGCC TAACACGCGAAAGGTCCCTGGATCAAAACCA GGCGGAAACAA349 Ile_AAT_chr6:276566-27656040 (+)CGGCCGGTTAGCTCAGTTGGTTAGAGCGTGG TGCTAATAACGCCAAGGTCGCGGGTTCGATC CCCGTACTGGCCA350 Gln_CTG_chr6:277134-27759206 (-)GGCCCCATGGTGTAATGGTCAGCACTCTGGA CTCTGAATCCAGCGATCCGAGTTCAAATCTC GGTGGGACCCA351 Gln_TTG_chr6: 277639-27763711 (-)GGCCCCATGGTGTAATGGTTAGCACTCTGGA CTTTGAATCCAGCGATCCGAGTTCAAATCTC GGTGGGACCTT352 Ala_AGC_chr6:285932-28575004 (+)TGGGGGTGTAGCTCAGTGGTAGAGCGCGTGC TTAGCATGTACGAGGTCCCGGGTTCAATCCC CGGCACCTCCA353 Ala_AGC_chr6:286013-28626085 (-)GGGGATGTAGCTCAGTGGTAGAGCGCATGCT TAGCATGCATGAGGTCCCGGGTTCGATCCCC AGCATCTCCAG354 Ala_CGC_chr6:286091-28697163 (+)AGGGGGTGTAGCTCAGTGGTAGAGCGCGTGC TTCGCATGTACGAGGCCCCGGGTTCGACCCC CGGCTCCTCCA355 Ala_AGC_chr6:288220-28806292 (-)GGGGGTGTAGCTCAGTGGTAGAGCGCGTGCT TAGCATGCACGAGGCCCCGGGTTCAATCCCC GGCACCTCCAT WO 2024/216206 PCT/US2024/024492 356 Ala_AGC_chr6:288461-28831533 (-)GGGGGTGTAGCTCAGTGGTAGAGCGCGTGCT TAGCATGCACGAGGCCCCGGGTTCAATCCCC GGCACCTCCAG357 Leu_CAA_chr6:288999-28864105 (-)GTCAGGATGGCCGAGTGGTCTAAGGCGCCAG ACTCAAGCTAAGCTTCCTCCGCGGTGGGGAT TCTGGTCTCCAATGGAGGCGTGGGTTCGAAT CCCACTTCTGACAC358 Leu_CAA_chr6:289829-28908934 (+)TGTCAGGATGGCCGAGTGGTCTAAGGCGCCA GACTCAAGCTTGGCTTCCTCGTGTTGAGGATT CTGGTCTCCAATGGAGGCGTGGGTTCGAATC CCACTTCTGACA359 Gin CTG chr6:289377-28909449 (-)GGTTCCATGGTGTAATGGTTAGCACTCTGGA CTCTGAATCCAGCGATCCGAGTTCAAATCTC GGTGGAACCTT360 Leu_AAG_chr6:281398-28911480 (-)GGTAGCGTGGCCGAGCGGTCTAAGGCGCTGG ATTAAGGCTCCAGTCTCTTCGGGGGCGTGGG TTCGAATCCCACCGCTGCCAG361 Met_CAT_chr6:289351-28912424 (+)TGCCTCCTTAGCGCAGTAGGCAGCGCGTCAG TCTCATAATCTGAAGGTCCTGAGTTCGAACCT CAGAGGGGGCA362 Lys_TTT_chr6:289805-28918878 (+)AGCCCGGATAGCTCAGTCGGTAGAGCATCAG ACTTTTAATCTGAGGGTCCAGGGTTCAAGTC CCTGTTCGGGCG363 Met_CAT_chr6: 289041-28921114 (-)GCCTCCTTAGCGCAGTAGGCAGCGCGTCAGT CTCATAATCTGAAGGTCCTGAGTTCGAACCT CAGAGGGGGCAG364 Glu_CTC_chr6 :289975-28950047 (+)TTCCCTGGTGGTCTAGTGGTTAGGATTCGGCG CTCTCACCGCCGCGGCCCGGGTTCGATTCCC GGTCAGGGAA365 Leu_TAA_chr6: 1447683-144537766 (+)CACCAGGATGGCCGAGTGGTTAAGGCGTTGG ACTTAAGATCCAATGGACATATGTCCGCGTG GGTTCGAACCCCACTCCTGGTA366 Pro_AGG_chr7: 1283503-128423575 (+)TGGCTCGTTGGTCTAGGGGTATGATTCTCGCT TAGGGTGCGAGAGGTCCCGGGTTCAAATCCC GGACGAGCCC367 Arg_CCT_chr7: 1395445-139025518 (+)AGCCCCAGTGGCCTAATGGATAAGGCATTGG CCTCCTAAGCCAGGGATTGTGGGTTCGAGTC CCATCTGGGGTG WO 2024/216206 PCT/US2024/024492 368 Cys_GCA_chr7: 1498271-149388343 (-)GGGGATATAGCTCAGGGGTAGAGCATTTGAC TGCAGATCAAGAGGTCCCCGGTTCAAATCCG GGTGCCCCCCC369 Tyr_GTA_chr8 :670601-67025694 (+)CCCTTCGATAGCTCAGCTGGTAGAGCGGAGG ACTGTAGCTACTTCCTCAGCAGGAGACATCC TTAGGTCGCTGGTTCGATTCCGGCTCGAAGG A370 Tyr_GTA_chr8 :670222-67026311 (+)CCCTTCGATAGCTCAGCTGGTAGAGCGGAGG ACTGTAGGCGCGCGCCCGTGGCCATCCTTAG GTCGCTGGTTCGATTCCGGCTCGAAGGA371 Ala_AGC_chr8 :670423-67026496 (+)TGGGGGATTAGCTCAAATGGTAGAGCGCTCG CTTAGCATGCGAGAGGTAGCGGGATCGATGC CCGCATCCTCCA372 Ser_AGA_chr8 :962884-96281966 (-)GTAGTCGTGGCCGAGTGGTTAAGGCGATGGA CTAGAAATCCATTGGGGTCTCCCCGCGCAGG TTCGAATCCTGCCGACTACGG373 Met_CAT_chr8:1249469-124169542 (-)GCCTCGTTAGCGCAGTAGGTAGCGCGTCAGTCTCATAATCTGAAGGTCGTGAGTTCGATCCTC ACACGGGGCAC374 Arg_TCT_chr9;1312354-131102445 (-)GGCTCTGTGGCGCAATGGATAGCGCATTGGA CTTCTAGCTGAGCCTAGTGTGGTCATTCAAA GGTTGTGGGTTCGAGTCCCACCAGAGTCGA375 Asn_GTT_chrlO:228437-22518511 (-)GTCTCTGTGGCGCAATCGGTTAGCGCGTTCG GCTGTTAACCGAAAGGTTGGTGGTTCGAGCC CACCCAGGGACGC376 Ser_TGA_chrlO:694260-69524342 (+)GGCAGCGATGGCCGAGTGGTTAAGGCGTTGG ACTTGAAATCCAATGGGGTCTCCCCGCGCAG GTTCGAACCCTGCTCGCTGCG377 ValTACchrl 1:598101-59318174 (-)GGTTCCATAGTGTAGTGGTTATCACGTCTGCT TTACACGCAGAAGGTCCTGGGTTCGAGCCCC AGTGGAACCAT378 ValTACchrl 1:598459-59318532 (-)GGTTCCATAGTGTAGCGGTTATCACGTCTGCT TTACACGCAGAAGGTCCTGGGTTCGAGCCCC AGTGGAACCAC379 ArgTCTchrl 1:59318766-59318852 (+)TGGCTCTGTGGCGCAATGGATAGCGCATTGG ACTTCTAGATAGTTAGAGAAATTCAAAGGTT GTGGGTTCGAGTCCCACCAGAGTCG WO 2024/216206 PCT/US2024/024492 380 LeuTAAchrl 1:599227-59319310(+)TACCAGAATGGCCGAGTGGTTAAGGCGTTGG ACTTAAGATCCAATGGATTCATATCCGCGTG GGTTCGAACCCCACTTCTGGTA381 LysTTTchrl 1:593901-59323974 (+)GGCCCGGATAGCTCAGTCGGTAGAGCATCAG ACTTTTAATCTGAGGGTCCGGGGTTCAAGTC CCTGTTCGGGCG382 Phe_GAA_chrl 1:59324969-59325042 (-)GCCGAAATAGCTCAGTTGGGAGAGCGTTAGA CTGAAGATCTAAAGGTCCCTGGTTCGATCCC GGGTTTCGGCAG383 LysTTTchrl 1:597807-59327880 (-)GCCCGGATAGCTCAGTCGGTAGAGCATCAGA CTTTTAATCTGAGGGTCCAGGGTTCAAGTCCC TGTTCGGGCGG384 PheGAAchrl 1:59333852-59333925 (-)GCCGAAATAGCTCAGTTGGGAGAGCGTTAGA CTGAAGATCTAAAGGTCCCTGGTTCAATCCC GGGTTTCGGCAG385 SerGCTchrl 1:66115590-66115672(+)GGACGAGGTGGCCGAGTGGTTAAGGCGATGGACTGCTAATCCATTGTGCTTTGCACGCGTGG GTTCGAATCCCATCCTCGTCG386 ProTGGchrl 1:75946868-75946940 (-)GGCTCGTTGGTCTAGGGGTATGATTCTCGGTT TGGGTCCGAGAGGTCCCGGGTTCAAATCCCG GACGAGCCCC387 Ser_CGA_chrl2:564147-56584229 (+)AGTCACGGTGGCCGAGTGGTTAAGGCGTTGG ACTCGAAATCCAATGGGGTTTCCCCGCACAG GTTCGAATCCTGTTCGTGACG388 Asp_GTC_chrl2:987280-98897352 (+)CTCCTCGTTAGTATAGTGGTTAGTATCCCCGC CTGTCACGCGGGAGACCGGGGTTCAATTCCC CGACGGGGAG389 Trp_CCA_chrl2:988029-98898101 (+)GGACCTCGTGGCGCAACGGTAGCGCGTCTGA CTCCAGATCAGAAGGCTGCGTGTTCGAATCA CGTCGGGGTCA390 Ala TGC chrl2: 1206300-125406372 (-)GGGGATGTAGCTCAGTGGTAGAGCGCATGCT TTGCATGTATGAGGCCCCGGGTTCGATCCCC GGCATCTCCAT391 Phe_GAA_chrl2:1212388-125412461 (-)GCCGAAATAGCTCAGTTGGGAGAGCGTTAGA CTGAAGATCTAAAGGTCCCTGGTTCGATCCC GGGTTTCGGCAG392 Ala_TGC_chrl2:1224511-125424583 (+)AGGGGATGTAGCTCAGTGGTAGAGCGCATGC TTTGCACGTATGAGGCCCCGGGTTCAATCCC CGGCATCTCCA WO 2024/216206 PCT/US2024/024492 393 Asn_GTT_chrl3:318100-31248174 (-)GTCTCTGTGGCGCAATCGGTTAGCGCGTTCG GCTGTTAACCGAAAGGTTGGTGGTTCGAGCC CACCCAGGGACGG394 Glu_TTC_chrl3:452061-45492133 (-)TCCCACATGGTCTAGCGGTTAGGATTCCTGGT TTTCACCCAGGCGGCCCGGGTTCGACTCCCG GTGTGGGAAC395 Thr_TGT_chrl4:211948-21082021 (-)GGCTCCATAGCTCAGGGGTTAGAGCGCTGGT CTTGTAAACCAGGGGTCGCGAGTTCAATTCT CGCTGGGGCCTG396 Leu_TAG_chrl4:213528-21093610 (+)TGGTAGTGTGGCCGAGCGGTCTAAGGCGCTG GATTTAGGCTCCAGTCTCTTCGGGGGCGTGG GTTCGAATCCCACCACTGCCA397 Thr_TGT_chrl4:219318-21099391 (-)GGCTCCATAGCTCAGGGGTTAGAGCACTGGT CTTGTAAACCAGGGGTCGCGAGTTCAAATCT CGCTGGGGCCTC398 Pro_TGG_chrl4:211164-21101236(+)TGGCTCGTTGGTCTAGTGGTATGATTCTCGCT TTGGGTGCGAGAGGTCCCGGGTTCAAATCCC GGACGAGCCC399 Tyr_GTA_chrl4:21 1350-21131444 (-)CCTTCGATAGCTCAGCTGGTAGAGCGGAGGA CTGTAGATTGTACAGACATTTGCGGACATCC TTAGGTCGCTGGTTCGATTCCGGCTCGAAGG AA400 ThrTGTchr 14:219848-21149921 (+)AGGCCCTATAGCTCAGGGGTTAGAGCACTGG TCTTGTAAACCAGGGGTCGCGAGTTCAAATC TCGCTGGGGCCT401 Tyr_GTA_chrl4:21 1431-21151520(+)TCCTTCGATAGCTCAGCTGGTAGAGCGGAGG ACTGTAGTACTTAATGTGTGGTCATCCTTAGG TCGCTGGTTCGATTCCGGCTCGAAGGA402 Pro_TGG_chrl4:212174-21152246(+)TGGCTCGTTGGTCTAGGGGTATGATTCTCGCT TTGGGTGCGAGAGGTCCCGGGTTCAAATCCC GGACGAGCCC403 Lys_CTT_chrl4:586612-58706685 (-)GCCCGGCTAGCTCAGTCGGTAGAGCATGGGA CTCTTAATCCCAGGGTCGTGGGTTCGAGCCC CACGTTGGGCGC404 Ile_AAT_chrl4: 1023428-102783502 (+)CGGCCGGTTAGCTCAGTTGGTTAGAGCGTGG TGCTAATAACGCCAAGGTCGCGGGTTCGATC CCCGTACGGGCCA WO 2024/216206 PCT/US2024/024492 405 Glu_TTC_chrl5:267380-26327452 (-)TCCCACATGGTCTAGCGGTTAGGATTCCTGGT TTTCACCCAGGCGGCCCGGGTTCGACTCCCG GTGTGGGAAT406 Ser_GCT_chrl5:406022-40886104 (-)GACGAGGTGGCCGAGTGGTTAAGGCGATGG ACTGCTAATCCATTGTGCTCTGCACGCGTGG GTTCGAATCCCATCCTCGTCGA 407 His_GTG_chrl5:450803-45490875 (-)GCCGTGATCGTATAGTGGTTAGTACTCTGCGT TGTGGCCGCAGCAACCTCGGTTCGAATCCGA GTCACGGCAT408 His_GTG_chrl5:453348-45493420 (+)CGCCGTGATCGTATAGTGGTTAGTACTCTGC GTTGTGGCCGCAGCAACCTCGGTTCGAATCC GAGTCACGGCA409 Gln_CTG_chrl5:661399-66161471 (-)GGTTCCATGGTGTAATGGTTAGCACTCTGGA CTCTGAATCCAGCGATCCGAGTTCAAATCTC GGTGGAACCTG410 Lys_CTT_chrl5:792903-79152976(+)TGCCCGGCTAGCTCAGTCGGTAGAGCATGGG ACTCTTAATCCCAGGGTCGTGGGTTCGAGCC CCACGTTGGGCG411 Arg_TCG_chrl5:898303-89878376 (+)GGGCCGCGTGGCCTAATGGATAAGGCGTCTG ACTTCGGATCAGAAGATTGCAGGTTCGAGTC CTGCCGCGGTCG412 Gly_CCC_chrl6:6835-686806 (-)GCGCCGCTGGTGTAGTGGTATCATGCAAGAT TCCCATTCTTGCGACCCGGGTTCGATTCCCGGGCGGCGCAC 413 Arg_CCG_chrl6;32674-3200747 (+)GGGCCGCGTGGCCTAATGGATAAGGCGTCTG ATTCCGGATCAGAAGATTGAGGGTTCGAGTC CCTTCGTGGTCG414 Arg_CCT_chr 16:32900-3202973 (+)CGCCCCGGTGGCCTAATGGATAAGGCATTGG CCTCCTAAGCCAGGGATTGTGGGTTCGAGTC CCACCCGGGGTA415 Lys_CTT_chrl6:32405-3207478 (-)GCCCGGCTAGCTCAGTCGGTAGAGCATGAGA CCCTTAATCTCAGGGTCGTGGGTTCGAGCCC CACGTTGGGCGT416 Thr_CGT_chrl6:149749-14379821 (+)AGGCGCGGTGGCCAAGTGGTAAGGCGTCGGT CTCGTAAACCGAAGATCACGGGTTCGAACCC CGTCCGTGCCT WO 2024/216206 PCT/US2024/024492 417 Leu_TAG_chr 16:227031-22207113 (-)GGTAGCGTGGCCGAGTGGTCTAAGGCGCTGG ATTTAGGCTCCAGTCATTTCGATGGCGTGGGT TCGAATCCCACCGCTGCCAC418 Leu_AAG_chrl6:208460-22308542 (+)GGGTAGCGTGGCCGAGCGGTCTAAGGCGCTG GATTAAGGCTCCAGTCTCTTCGGGGGCGTGG GTTCGAATCCCACCGCTGCCA 419 Leu_CAG_chrl 6:573862-57333945 (+)AGTCAGGATGGCCGAGCGGTCTAAGGCGCTG CGTTCAGGTCGCAGTCTCCCCTGGAGGCGTG GGTTCGAATCCCACTTCTGACA420 Leu_C AGchr 16:574391-57334474 (-)GTCAGGATGGCCGAGCGGTCTAAGGCGCTGC GTTCAGGTCGCAGTCTCCCCTGGAGGCGTGG GTTCGAATCCCACTTCTGACAG421 Met_CAT_chrl6:877627-87417700 (-)GCCTCGTTAGCGCAGTAGGCAGCGCGTCAGT CTCATAATCTGAAGGTCGTGAGTTCGAGCCT CACACGGGGCAG422 Leu_TAG_chrl7:80631-8023713 (-)GGTAGCGTGGCCGAGCGGTCTAAGGCGCTGG ATTTAGGCTCCAGTCTCTTCGGAGGCGTGGG TTCGAATCCCACCGCTGCCAG423 Arg_TCT_chrl7:80242-8024330 (+)TGGCTCTGTGGCGCAATGGATAGCGCATTGG ACTTCTAGTGACGAATAGAGCAATTCAAAGG TTGTGGGTTCGAATCCCACCAGAGTCG 424 Gly_GCC_chrl7:80063-8029134 (+)CGCATTGGTGGTTCAGTGGTAGAATTCTCGC CTGCCACGCGGGAGGCCCGGGTTCGATTCCC GGCCAATGCA425 Ser_CGA_chrl7:80198-8042280 (-)GCTGTGATGGCCGAGTGGTTAAGGCGTTGGA CTCGAAATCCAATGGGGTCTCCCCGCGCAGG TTCGAATCCTGCTCACAGCGT426 Thr_AGT_chrl7:80769-8042843 (-)GGCGCCGTGGCTTAGCTGGTTAAAGCGCCTG TCTAGTAAACAGGAGATCCTGGGTTCGAATC CCAGCGGTGCCTG427 Trp CCA chrl7:80675-8089747 (+)CGACCTCGTGGCGCAACGGTAGCGCGTCTGA CTCCAGATCAGAAGGTTGCGTGTTCAAATCA CGTCGGGGTCA428 Ser_GCT_chrl7:80183-8090265 (+)AGACGAGGTGGCCGAGTGGTTAAGGCGATG GACTGCTAATCCATTGTGCTCTGCACGCGTG GGTTCGAATCCCATCCTCGTCG WO 2024/216206 PCT/US2024/024492 429 Thr_AGT_chrl7:80477-8090551 (+)CGGCGCCGTGGCTTAGTTGGTTAAAGCGCCTGTCTAGTAAACAGGAGATCCTGGGTTCGAAT CCCAGCGGTGCCT430 Trp_CCA_chrl7:81186-8124258 (-)GGCCTCGTGGCGCAACGGTAGCGCGTCTGAC TCCAGATCAGAAGGTTGCGTGTTCAAATCAC GTCGGGGTCAA431 Gly_TCC_chrl7:81865-8124937 (+)AGCGTTGGTGGTATAGTGGTAAGCATAGCTG CCTTCCAAGCAGTTGACCCGGGTTCGATTCCC GGCCAACGCA432 Asp_GTC_chrl7:81555-8125627 (-)TCCTCGTTAGTATAGTGGTGAGTATCCCCGCC TGTCACGCGGGAGACCGGGGTTCGATTCCCC GACGGGGAGA433 Pro_CGG_chrl7:81150-8126222 (-)GGCTCGTTGGTCTAGGGGTATGATTCTCGCTT CGGGTGCGAGAGGTCCCGGGTTCAAATCCCG GACGAGCCCT434 Thr_AGT_chrl7:81552-8129626 (-)GGCGCCGTGGCTTAGTTGGTTAAAGCGCCTG TCTAGTAAACAGGAGATCCTGGGTTCGAATC CCAGCGGTGCCTT435 Ser_AGA_chrl7:81927-8130009 (-)GTAGTCGTGGCCGAGTGGTTAAGGCGATGGA CTAGAAATCCATTGGGGTCTCCCCGCGCAGG TTCGAATCCTGCCGACTACGT436 Trp_CCA_chrl7:191493-19411565 (+)TGACCTCGTGGCGCAATGGTAGCGCGTCTGA CTCCAGATCAGAAGGTTGCGTGTTCAAGTCA CGTCGGGGTCA437 ThrCGTchrl 7:297092-29877164 (+)AGGCGCGGTGGCCAAGTGGTAAGGCGTCGGT CTCGTAAACCGAAGATCGCGGGTTCGAACCC CGTCCGTGCCT438 Cys_GCA_chrl7:373897-37023969 (+)AGGGGGTATAGCTCAGTGGTAGAGCATTTGA CTGCAGATCAAGAGGTCCCCGGTTCAAATCC GGGTGCCCCCT439 Cys_GCA_chrl 7:375544-37025616 (-)GGGGGTATAGCTCAGTGGTAGAGCATTTGAC TGCAGATCAAGAGGTCCCTGGTTCAAATCCG GGTGCCCCCTC440 Cys_GCA_chr 17:379986-37310058 (-)GGGGGTATAGCTCAGTGGTAGAGCATTTGAC TGCAGATCAAGAGGTCCCCGGTTCAAATCCG GGTGCCCCCTC441 Gln_TTG_chrl7:479889-47269961 (+)AGGTCCCATGGTGTAATGGTTAGCACTCTGG ACTTTGAATCCAGCGATCCGAGTTCAAATCT CGGTGGGACCT WO 2024/216206 PCT/US2024/024492 442 ArgCCGchr 17:666012-66016085 (-)GACCCAGTGGCCTAATGGATAAGGCATCAGC CTCCGGAGCTGGGGATTGTGGGTTCGAGTCC CATCTGGGTCGC443 Arg_CCT_chrl7:730000-73030073 (+)AGCCCCAGTGGCCTAATGGATAAGGCACTGG CCTCCTAAGCCAGGGATTGTGGGTTCGAGTC CCACCTGGGGTA444 Arg_CCT_chrl7:730525-73030598 (-)GCCCCAGTGGCCTAATGGATAAGGCACTGGC CTCCTAAGCCAGGGATTGTGGGTTCGAGTCC CACCTGGGGTGT445 Arg_TCG_chr 17:731207-73031280(+)AGACCGCGTGGCCTAATGGATAAGGCGTCTG ACTTCGGATCAGAAGATTGAGGGTTCGAGTC CCTTCGTGGTCG446 Asn_GTT_chrl9:13561-1383635 (+)CGTCTCTGTGGCGCAATCGGTTAGCGCGTTC GGCTGTTAACCGAAAGGTTGGTGGTTCGAGC CCACCCAGGGACG447 Gly_TCC_chrl9:47081-4724153 (+)GGCGTTGGTGGTATAGTGGTTAGCATAGCTG CCTTCCAAGCAGTTGACCCGGGTTCGATTCCC GGCCAACGCA448 Val_CAC_chrl9:47646-4724719 (-)GTTTCCGTAGTGTAGCGGTTATCACATTCGCC TCACACGCGAAAGGTCCCCGGTTCGATCCCG GGCGGAAACAG449 Thr_AGT_chrl9:337962-33668036 (+)TGGCGCCGTGGCTTAGTTGGTTAAAGCGCCT GTCTAGTAAACAGGAGATCCTGGGTTCGAAT CCCAGCGGTGCCT450 Ile_TAT_chrl9:399807-39902900 (-)GCTCCAGTGGCGCAATCGGTTAGCGCGCGGT ACTTATATGACAGTGCGAGCGGAGCAATGCC GAGGTTGTGAGTTCGATCCTCACCTGGAGCA C451 Gly_GCC_chr21:18827106-18827177 (-)GCATGGGTGGTTCAGTGGTAGAATTCTCGCC TGCCACGCGGGAGGCCCGGGTTCGATTCCCG GCCCATGCAG Nucleotide Sequence Modifications The present disclosure describes TREMs comprising a nucleotide sequence modification, e.g., relative to a first TREM nucleotide sequence, that may modulate a functional parameter of the TREM. These TREMs may further comprise a non-naturally occurring chemical modification, or may not. For example, a TREM comprising a nucleotide sequence modification may exhibit improved activity or stability, e.g., in vitro or in a cell. The nucleotide sequence WO 2024/216206 PCT/US2024/024492 modification may be a nucleotide substitution, e.g., a change of a nucleotide at a given position in the TREM sequence to a different nucleotide. In an embodiment, the nucleotide substitution is an A to U substitution. In an embodiment, the nucleotide substitution is an A to G substitution. In an embodiment, the nucleotide substitution is an A to C substitution. In an embodiment, the nucleotide substitution is a U to A substitution. In an embodiment, the nucleotide substitution is a U to G substitution. In an embodiment, the nucleotide substitution is a U to C substitution. In an embodiment, the nucleotide substitution is a G to A substitution. In an embodiment, the nucleotide substitution is a G to U substitution. In an embodiment, the nucleotide substitution is a Gto C substitution. In an embodiment, the nucleotide substitution is a C to A substitution. In an embodiment, the nucleotide substitution is a C to U substitution. In an embodiment, the nucleotide substitution is a C to G substitution.In one aspect, the present disclosure features a TREM comprising a nucleotide substitution at a nucleotide within the TREM sequence. In an embodiment, the nucleotide substitution is within a domain of the TREM, e.g., the [ASt Domain 1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], or the [ASt Domain2]. In an embodiment, the nucleotide substitution is within the [ASt Domainl]. In an embodiment, the nucleotide substitution is within the [DH Domain], In an embodiment, the nucleotide substitution is within the [ACH Domain], In an embodiment, the nucleotide substitution is within the [VL Domain], In an embodiment, the nucleotide substitution is within the [TH Domain], In an embodiment, the nucleotide substitution is within the [ASt Domain2], In an embodiment, the nucleotide substitution is at any of positions 1, 2, 3, 4, 5, 6, 7, 8, or 9 within the [ASt Domainl], In an embodiment, the nucleotide substitution is at any of positions 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26 within the [DH Domain], In an embodiment, the nucleotide substitution is at any of positions 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, or within the [ACH Domain], In an embodiment, the nucleotide substitution is at any of positions 44, 45, 46, 47, 48, or 49 within the [VL Domain], In an embodiment, the nucleotide substitution is at any of positions 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, or within the [TH Domain], In an embodiment, the nucleotide substitution is at any of positions 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, or 76 within the [ASt Domain2], In an embodiment, a nucleotide substitution is at a position within the TREM sequence, e.g., nucleotide position 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, WO 2024/216206 PCT/US2024/024492 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 1 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 2 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 3 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 4 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 5 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 6 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 7 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 8 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 9 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 10 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 11 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 12 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 13 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 14 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 15 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 16 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 17 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 18 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 19 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 20 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 21 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 22 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 23 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 24 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 25 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 26 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 27 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 28 within the TREM WO 2024/216206 PCT/US2024/024492 sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide substitution is at position 29 within the TREM substitution is at position 30 within the TREM substitution is at position 31 within the TREM substitution is at position 32 within the TREM substitution is at position 33 within the TREM substitution is at position 34 within the TREM substitution is at position 35 within the TREM substitution is at position 36 within the TREM substitution is at position 37 within the TREM substitution is at position 38 within the TREM substitution is at position 39 within the TREM substitution is at position 40 within the TREM substitution is at position 41 within the TREM substitution is at position 42 within the TREM substitution is at position 43 within the TREM substitution is at position 44 within the TREM substitution is at position 45 within the TREM substitution is at position 46 within the TREM substitution is at position 47 within the TREM substitution is at position 48 within the TREM substitution is at position 49 within the TREM substitution is at position 50 within the TREM substitution is at position 51 within the TREM substitution is at position 52 within the TREM substitution is at position 53 within the TREM substitution is at position 54 within the TREM substitution is at position 55 within the TREM substitution is at position 56 within the TREM substitution is at position 57 within the TREM substitution is at position 58 within the TREM substitution is at position 59 within the TREM WO 2024/216206 PCT/US2024/024492 sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide sequence. In an embodiment, the nucleotide substitution is at position 60 within the TREM substitution is at position 61 within the TREM substitution is at position 62 within the TREM substitution is at position 63 within the TREM substitution is at position 64 within the TREM substitution is at position 65 within the TREM substitution is at position 66 within the TREM substitution is at position 67 within the TREM substitution is at position 68 within the TREM substitution is at position 69 within the TREM substitution is at position 70 within the TREM substitution is at position 71 within the TREM substitution is at position 72 within the TREM substitution is at position 73 within the TREM substitution is at position 74 within the TREM substitution is at position 75 within the TREM substitution is at position 76 within the TREM substitution is at position 77 within the TREM substitution is at position 78 within the TREM substitution is at position 79 within the TREM substitution is at position 80 within the TREM substitution is at position 81 within the TREM substitution is at position 82 within the TREM substitution is at position 83 within the TREM substitution is at position 84 within the TREM substitution is at position 85 within the TREM substitution is at position 86 within the TREM substitution is at position 87 within the TREM substitution is at position 88 within the TREM substitution is at position 89 within the TREM substitution is at position 90 within the TREM WO 2024/216206 PCT/US2024/024492 sequence. In an embodiment, the nucleotide substitution is at position 91 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 92 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 93 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 94 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 95 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 96 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 97 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 98 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 99 within the TREM sequence. In an embodiment, the nucleotide substitution is at position 100 within the TREM sequence. In an embodiment, a TREM comprises multiple nucleotide substitutions, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more nucleotide substitutions. In an embodiment, a TREM comprises 1 nucleotide substitution. In an embodiment, a TREM comprises 2 nucleotide substitutions. In an embodiment, a TREM comprises 3 nucleotide substitutions. In an embodiment, a TREM comprises 4 nucleotide substitutions. In an embodiment, a TREM comprises 5 nucleotide substitutions. In an embodiment, a TREM comprises 6 nucleotide substitutions. In an embodiment, a TREM comprises 7 nucleotide substitutions. In an embodiment, a TREM comprises 8 nucleotide substitutions. In an embodiment, a TREM comprises 9 nucleotide substitutions. In an embodiment, a TREM comprises 10 nucleotide substitutions. In an embodiment, a TREM comprises 11 nucleotide substitutions. In an embodiment, a TREM comprises 12 nucleotide substitutions. In an embodiment, a TREM comprises 13 nucleotide substitutions. In an embodiment, a TREM comprises 14 nucleotide substitutions. In an embodiment, a TREM comprises 15 nucleotide substitutions. In an embodiment, a TREM comprises 16 nucleotide substitutions. In an embodiment, a TREM comprises 17 nucleotide substitutions. In an embodiment, a TREM comprises 18 nucleotide substitutions. In an embodiment, a TREM comprises 19 nucleotide substitutions. In an embodiment, a TREM comprises 20 nucleotide substitutions. In an embodiment, a TREM comprises more than 20 nucleotide substitutions. In an embodiment, a TREM comprises nucleotide substitutions in more than one TREM domain, e.g., more than one of [ASt Domain 1], [DH Domain], [ACH Domain], [VL Domain], [TH Domain], or [ASt Domain2]. In an embodiment, a TREM comprises nucleotide substitutions in one TREM WO 2024/216206 PCT/US2024/024492 domain. In an embodiment, a TREM comprises nucleotide substitutions in two TREM domains. In an embodiment, a TREM comprises nucleotide substitutions in three TREM domains. In an embodiment, a TREM comprises nucleotide substitutions in four TREM domains. In an embodiment, a TREM comprises nucleotide substitutions in five TREM domains. In an embodiment, a TREM comprises nucleotide substitutions in six TREM domains. In an embodiment, a TREM comprises nucleotide substitutions in the [ASt Domainl] and the [DH Domain], In an embodiment, a TREM comprises nucleotide substitutions in the [ASt Domainl] and the [ACH Domain], In an embodiment, a TREM comprises nucleotide substitutions in the [ASt Domainl] and the [VL Domain], In an embodiment, a TREM comprises nucleotide substitutions in the [ASt Domainl] and the [TH Domain], In an embodiment, a TREM comprises nucleotide substitutions in the [ASt Domainl] and the [ASt Domain2], In an embodiment, a TREM comprises nucleotide substitutions in the [DH Domain] and the [ACH Domain], In an embodiment, a TREM comprises nucleotide substitutions in the [DH Domain] and the [ACH Domain], In an embodiment, a TREM comprises nucleotide substitutions in the [DH Domain] and the [VL Domain], In an embodiment, a TREM comprises nucleotide substitutions in the [DH Domain] and the [TH Domain], In an embodiment, a TREM comprises nucleotide substitutions in the [DH Domain] and the [ASt Domain2], In an embodiment, a TREM comprises nucleotide substitutions in the [ACH Domain] and the [VL Domain], In an embodiment, a TREM comprises nucleotide substitutions in the [ACH Domain] and the [TH Domain], In an embodiment, a TREM comprises nucleotide substitutions in the [ACH Domain] and the [ASt Domain2], In an embodiment, a TREM comprises nucleotide substitutions in the [VL Domain] and the [TH Domain], In an embodiment, a TREM comprises nucleotide substitutions in the [VL Domain] and the [ASt Domain2], In an embodiment, a TREM comprises nucleotide substitutions in the [TH Domain] and the [ASt Domain2], In an embodiment, a TREM comprises nucleotide substitutions in the [ASt Domainl] and the [ASt Domain!]. In an embodiment, a TREM comprises nucleotide substitutions in the [DH Domain] and the [DH Domain], In an embodiment, a TREM comprises nucleotide substitutions in the [ACH Domain] and the [ACH Domain], In an embodiment, a TREM comprises nucleotide substitutions in the [VL Domain] and the [VL Domain], In an embodiment, a TREM comprises nucleotide substitutions in the [TH Domain] and the [TH Domain], In an embodiment, a TREM comprises nucleotide substitutions in the [ASt Domain2] and the [ASt Domain2], In an embodiment, the nucleotide substitution is WO 2024/216206 PCT/US2024/024492 within a loop of the TREM secondary structure, e.g., an unpaired region of the TREM. In an embodiment, the nucleotide substitution is at any of unpaired positions 8, 9, 14, 15, 16, 17, 17A, 18, 19, 20, 20A, 20B, 21, 32, 33, 34, 35, 36, 37, 38, 45, ell, el2, 613, el4, el5, el6, el7, el, e2, 63, e4, e5, 627, e26, e25, 624, 623, 622, 621, 46, 47, 48, 54, 55, 56, 57, 58, 59, 60, 73, 74, 75, or according to the universal tRNA numbering scheme, e.g., the nucleotide position numbering as provided in FIG. 4. In an embodiment, the nucleotide substitution is within a stem of the TREM secondary structure, e.g., within a base-paired region of the TREM. In an embodiment, the nucleotide substitution is at any of base-paired positions 1, 2, 3, 4, 5, 6, 7, 10, 11, 12, 13, 22, 23, 24, 25, 27, 28, 29, 30, 31, 39, 40, 41, 42, 43, 49, 50, 51, 52, 53, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, or 72 according to the universal tRNA numbering scheme, e.g., the nucleotide position numbering as provided in FIG. 4. In an embodiment, a nucleotide substitution maintains the secondary structure, e.g., base-pairing, of the TREM. In an embodiment, a nucleotide substitution does not maintain the secondary structure, e.g., base-pairing, of the TREM. In an embodiment, a TREM comprising a first nucleotide substitution at a base-paired position further comprises a second compensatory nucleotide substitution, e.g., a nucleotide substitution at the second position that maintains base-pairing with the first nucleotide substitution. In an embodiment, the compensatory nucleotide substitution for a first A nucleotide substitution is a U. In an embodiment, the compensatory nucleotide substitution for a first U nucleotide substitution is an A. In an embodiment, the compensatory nucleotide substitution for a first G nucleotide substitution is a C. In an embodiment, the compensatory nucleotide substitution for a first C nucleotide substitution is a G. In an embodiment, both nucleotide positions of a base-pair comprise nucleotide substitutions, e.g., both nucleotide positions of any ofbase-pairs 1:72, 2:71, 3:70, 4:69, 5:68, 6:67, 7:66, 10:25, 11:24, 12:23, 13:22, 27:43, 28:42, 29:41, 30:40, 31:39, 49:65, 50:64, 51:63, 52:62, or 53:61, wherein the number preceding the colon represents the first nucleotide position of the base-pair and the number following the colon represents the second nucleotide position of the base-pair. In an embodiment, both nucleotides of the base-pair at positions 1 and 72 comprise nucleotide substitutions. In an embodiment, both nucleotides of the base-pair at positions 2 and 71 comprise nucleotide substitutions. In an embodiment, both nucleotides of the base-pair at positions 3 and 70 comprise nucleotide substitutions. In an embodiment, both nucleotides of the base-pair at positions 4 and 69 comprise nucleotide substitutions. In an embodiment, both nucleotides of the base-pair at positions 5 and WO 2024/216206 PCT/US2024/024492 68 comprise nucleotide substitutions. In an embodiment, both nucleotides of the base-pair at positions 6 and 67 comprise nucleotide substitutions. In an embodiment, both nucleotides of the base-pair at positions 7 and 68 comprise nucleotide substitutions. In an embodiment, both nucleotides of the base-pair at positions 10 and 25 comprise nucleotide substitutions. In an embodiment, both nucleotides of the base-pair at positions 11 and 24 comprise nucleotide substitutions. In an embodiment, both nucleotides of the base-pair at positions 12 and comprise nucleotide substitutions. In an embodiment, both nucleotides of the base-pair at positions 13 and 22 comprise nucleotide substitutions. In an embodiment, both nucleotides of the base-pair at positions 27 and 43 comprise nucleotide substitutions. In an embodiment, both nucleotides of the base-pair at positions 28 and 42 comprise nucleotide substitutions. In an embodiment, both nucleotides of the base-pair at positions 29 and 41 comprise nucleotide substitutions. In an embodiment, both nucleotides of the base-pair at positions 30 and comprise nucleotide substitutions. In an embodiment, both nucleotides of the base-pair at positions 31 and 39 comprise nucleotide substitutions. In an embodiment, both nucleotides of the base-pair at positions 49 and 65 comprise nucleotide substitutions. In an embodiment, both nucleotides of the base-pair at positions 50 and 64 comprise nucleotide substitutions. In an embodiment, both nucleotides of the base-pair at positions 51 and 63 comprise nucleotide substitutions. In an embodiment, both nucleotides of the base-pair at positions 52 and comprise nucleotide substitutions. In an embodiment, both nucleotides of the base-pair at positions 53 and 61 comprise nucleotide substitutions. In an embodiment, a TREM comprises multiple pairs of nucleotide substitutions and compensatory nucleotide substitutions, e.g., multiple pairs of nucleotide substitutions that maintain base pairing, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more pairs of nucleotide substitutions and compensatory nucleotide substitutions. In an embodiment, a TREM comprises 1 pair of a nucleotide substitution and a compensatory nucleotide substitution. In an embodiment, a TREM comprises 2 pairs of a nucleotide substitution and a compensatory nucleotide substitution. In an embodiment, a TREM comprises pairs of a nucleotide substitution and a compensatory nucleotide substitution. In an embodiment, a TREM comprises 4 pairs of a nucleotide substitution and a compensatory nucleotide substitution. In an embodiment, a TREM comprises 5 pairs of a nucleotide substitution and a compensatory nucleotide substitution. In an embodiment, a TREM comprises pairs of a nucleotide substitution and a compensatory nucleotide substitution. In an WO 2024/216206 PCT/US2024/024492 embodiment, a TREM comprises 7 pairs of a nucleotide substitution and a compensatory nucleotide substitution. In an embodiment, a TREM comprises 8 pairs of a nucleotide substitution and a compensatory nucleotide substitution. In an embodiment, a TREM comprises pairs of a nucleotide substitution and a compensatory nucleotide substitution. In an embodiment, a TREM comprises 10 pairs of a nucleotide substitution and a compensatory nucleotide substitution. In an embodiment, a TREM comprises more than 10 pairs of a nucleotide substitution and a compensatory nucleotide substitution. In an embodiment, the nucleotide substitutions at a first position and a second compensatory position result in a lower energy base pair, e.g., a change from a G:C or C:G base pair to an A:U or U:A base pair. In an embodiment, the nucleotide substitutions at a first position and a second compensatory position result in a higher energy base pair, e.g., a change from an A:U or U:A base pair to a G:C or C:G base pair. In an embodiment, the nucleotide substitutions at a first position and a second compensatory position result in a neutral energy base pair, e.g., a change from an A:U base pair to a U:A base pair or a C:G base pair to a G:C base pair. In an embodiment, a nucleotide substitution results in a wobble base pair, e.g., a G:U base pair. In an embodiment, the nucleotide substitutions at a first position and a second compensatory position result in a wobble base pair, e.g., a G:U base pair. In an embodiment, a nucleotide substitution disrupts base-pairing.In an embodiment, a nucleotide substitution results in modulation of the activity of the TREM, e.g., results in an increase or a decrease in activity of the TREM. For example, a nucleotide substitution may modulate the ability of the TREM to (i) support protein synthesis, (ii) be charged by a tRNA synthetase, (iii) be bound by an elongation factor, (iv) introduce an amino acid into a peptide chain, (v) support protein elongation, (vi) support initiation of protein synthesis, or (vii) read-through a premature termination codon (PTC), e.g., in a cell. In an embodiment, a nucleotide substitution modulates the ability of a TREM to support protein synthesis. In an embodiment, a nucleotide substitution modulates the ability of a TREM to be charged by a tRNA synthetase. In an embodiment, a nucleotide substitution modulates the ability of a TREM to be bound by an elongation factor. In an embodiment, a nucleotide substitution modulates the ability of a TREM to introduce an amino acid into a peptide chain. In an embodiment, a nucleotide substitution modulates the ability of a TREM to support protein elongation. In an embodiment, a nucleotide substitution modulates the ability of a TREM to support initiation of protein synthesis. In an embodiment, a nucleotide substitution modulates the WO 2024/216206 PCT/US2024/024492 ability of a TREM to read-through a PTC. In an embodiment, a nucleotide substitution at a particular position in the TREM results in an increase in the capability of the TREM to support protein synthesis, e.g., in a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in an increase in the capability of the TREM to be charged by a tRNA synthetase, e.g., in a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in an increase in the capability of the TREM to be bound by an elongation factor, e.g., in a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in an increase in the capability of the TREM to introduce an amino acid into a peptide chain, e.g., in a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in an increase in the capability of the TREM to support protein elongation, e.g., in a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in an increase in the capability of the TREM to support initiation of protein synthesis, e.g., in a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in an increase in the capability of the TREM to read-through a premature termination codon, e.g., in a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in a decrease in the capability of the TREM to support protein synthesis, e.g., in a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, WO 2024/216206 PCT/US2024/024492 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in a decrease in the capability of the TREM to be charged by a tRNA synthetase, e.g., in a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in a decrease in the capability of the TREM to be bound by an elongation factor, e.g., in a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in a decrease in the capability of the TREM to introduce an amino acid into a peptide chain, e.g., in a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in a decrease in the capability of the TREM to support protein elongation, e.g., in a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in a decrease in the capability of the TREM to support initiation of protein synthesis, e.g., in a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in a decrease in the capability of the TREM to read-through a premature termination codon, e.g., in a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard.In an embodiment, a nucleotide substitution results in modulation of the stability of the TREM, e.g., results in an increase or a decrease in stability of the TREM. For example, a nucleotide substitution may modulate the (i) localization of the TREM, (ii) the amount of time before the TREM is degraded, (iii) the amount of time the TREM is charged with an amino acid, (iv) the amount of time the TREM interacts with a ribosome, (v) the amount of time the TREM WO 2024/216206 PCT/US2024/024492 interacts with an elongation factor, (vi) modification of the TREM, or (vii) interaction of the TREM with tRNA degradation proteins, e.g., within a cell. In an embodiment, a nucleotide substitution modulates the localization of a TREM. In an embodiment, a nucleotide substitution modulates the amount of time before the TREM is degraded. In an embodiment, a nucleotide substitution modulates the amount of time the TREM is charged with an amino acid. In an embodiment, a nucleotide substitution modulates the amount of time the TREM interacts with a ribosome. In an embodiment, a nucleotide substitution modulates the amount of time the TREM interacts with an elongation factor. In an embodiment, a nucleotide substitution modulates modification of a TREM. In an embodiment, a nucleotide substitution modulates interaction of the TREM with tRNA degradation proteins. In an embodiment, a nucleotide substitution at a particular position in the TREM results in an increase in proper localization of a TREM, e.g., within a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in an increase in the amount of time before a TREM is degraded, e.g., within a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in an increase in the amount of time a TREM is charged with an amino acid, e.g., within a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in an increase in the amount of time a TREM interacts with a ribosome, e.g., within a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in an increase in the amount of time a TREM interacts with an elongation factor, e.g., within a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in an increase in modification of a TREM, e.g., within a cell, e.g., by about 1%, WO 2024/216206 PCT/US2024/024492 %, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in an increase in interaction of the TREM with tRNA degradation proteins, e.g., within a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in a decrease in proper localization of a TREM, e.g., within a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in a decrease in the amount of time before a TREM is degraded, e.g., within a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in a decrease in the amount of time a TREM is charged with an amino acid, e.g., within a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in a decrease in the amount of time a TREM interacts with a ribosome, e.g., within a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in a decrease in the amount of time a TREM interacts with an elongation factor, e.g., within a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in a decrease in modification of a TREM, e.g., within a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard. In an embodiment, a nucleotide substitution at a particular position in the TREM results in a decrease in interaction of the TREM with tRNA degradation WO 2024/216206 PCT/US2024/024492 proteins, e.g., within a cell, e.g., by about 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 99.5%, 99.9%, or more, e.g., relative to a reference standard.Exemplary nucleotide sequence modifications are outlined below.A TREM may comprise a nucleotide mutation relative to the nucleotide sequence of SEQ ID NO: 734. In an embodiment, the nucleotide mutation relative to the nucleotide sequence of SEQ ID NO: 734 is a nucleotide substitution. In an embodiment, the TREM comprises a nucleotide substitution relative to the nucleotide sequence of SEQ ID NO: 734 in the [VL Domain], In an embodiment, the TREM comprises one nucleotide substitution. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 40 and 50. In an embodiment, the nucleotide substitution is at nucleotide position 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50. In an embodiment, the nucleotide substitution is at position 44. In an embodiment, the nucleotide substitution is an A to G substitution. In an embodiment, the nucleotide substitution is A44G. In an embodiment, the TREM has the nucleotide sequence of SEQ ID NO: 743. In an embodiment, the TREM having SEQ ID NO: 743 comprises a non- naturally occurring modification. In an embodiment, the TREM having SEQ ID NO: 743 has a non-naturally occurring modification listed in Table 6, e.g., one of Pattern Nos: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21,22, 23,24, 25,26, 27, 28, 29, 30, 31, and 32.A TREM may comprise a nucleotide substitution relative to the nucleotide sequence of SEQ ID NO: 734, wherein the nucleotide substitution relative to the nucleotide sequence of SEQ ID NO: 734 is present in each of [ASt Domainl] and the [ASt Domain2]. In an embodiment, the TREM comprises eight nucleotide substitutions. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 1 and 10. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 60 and 70. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 70 and 80. In an embodiment, the nucleotide substitution is at nucleotide position 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In an embodiment, the nucleotide substitution is at nucleotide position 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70. In an embodiment, the nucleotide substitution is at nucleotide position 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80. In an embodiment, the nucleotide substitution is at position 2. In an embodiment, the nucleotide substitution is at position 4. In an embodiment, the nucleotide substitution is at position 5 . In an embodiment, the nucleotide substitution is at WO 2024/216206 PCT/US2024/024492 position 6. In an embodiment, the nucleotide substitution is at position 67. In an embodiment, the nucleotide substitution is at position 68. In an embodiment, the nucleotide substitution is at position 69. In an embodiment, the nucleotide substitution is at position 71. In an embodiment, the nucleotide substitution is a Gto C substitution. In an embodiment, the nucleotide substitution is a U to C substitution. In an embodiment, the nucleotide substitution is a C to G substitution. In an embodiment, the nucleotide substitution is a C to A substitution. In an embodiment, the nucleotide substitution is a G to U substitution. In an embodiment, the nucleotide substitution is an A to G substitution. In an embodiment, the nucleotide substitution is a U to G substitution. In an embodiment, the nucleotide substitution is G2C. In an embodiment, the nucleotide substitution is U4C. In an embodiment, the nucleotide substitution is C5G. In an embodiment, the nucleotide substitution is C6A. In an embodiment, the nucleotide substitution is G67U. In an embodiment, the nucleotide substitution is G68C. In an embodiment, the nucleotide substitution is A69G. In an embodiment, the nucleotide substitution is U71G. In an embodiment, the TREM has the nucleotide sequence of SEQ ID NO; 639. In an embodiment, the TREM having SEQ ID NO: 639 comprises a non-naturally occurring modification. In an embodiment, the TREM having SEQ ID NO; 639 has a non-naturally occurring modification listed in Table 6, e.g., one of Pattern Nos: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, and 32.A TREM may comprise a nucleotide substitution relative to the nucleotide sequence of SEQ ID NO: 734, wherein the nucleotide substitution is present in each of the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], and the [ASt Domain2]. in an embodiment, the TREM comprises seventeen nucleotide substitutions. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 1 and 10. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 10 and 20. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 20 and 30. In an embodiment, the nucleotide substitution is at a nucleotide position between positions and 40. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 40 and 50. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 60 and 70. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 70 and 80. In an embodiment, the nucleotide substitution is at nucleotide position 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In an embodiment, the nucleotide substitution is WO 2024/216206 PCT/US2024/024492 at nucleotide position 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In an embodiment, the nucleotide substitution is at nucleotide position 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. In an embodiment, the nucleotide substitution is at nucleotide position 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40. In an embodiment, the nucleotide substitution is at nucleotide position 40, 41, 41, 43, 44, 45, 46, 47, 48, 49, or 50. In an embodiment, the nucleotide substitution is at nucleotide position 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, and 70. In an embodiment, the nucleotide substitution is at nucleotide position 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80. In an embodiment, the nucleotide substitution is at position 2. In an embodiment, the nucleotide substitution is at position 12. In an embodiment, the nucleotide substitution is at position 13. In an embodiment, the nucleotide substitution is at position 22. In an embodiment, the nucleotide substitution is at position 23. In an embodiment, the nucleotide substitution is at position 28. In an embodiment, the nucleotide substitution is at position 31. In an embodiment, the nucleotide substitution is at position 39. In an embodiment, the nucleotide substitution is at position 40. In an embodiment, the nucleotide substitution is at position 42. In an embodiment, the nucleotide substitution is at position 43. In an embodiment, the nucleotide substitution is at position 44. In an embodiment, the nucleotide substitution is at position 46. In an embodiment, the nucleotide substitution is at position 49. In an embodiment, the nucleotide substitution is at position 65. In an embodiment, the nucleotide substitution is at position 71. In an embodiment, the nucleotide substitution is at position 72. In an embodiment, the nucleotide substitution is a G to C substitution. In an embodiment, the nucleotide substitution is a C to U substitution. In an embodiment, the nucleotide substitution is a G to A substitution. In an embodiment, the nucleotide substitution is a C to G substitution. In an embodiment, the nucleotide substitution is a U to C substitution. In an embodiment, the nucleotide substitution is an A to C substitution. In an embodiment, the nucleotide substitution is a U to G substitution. In an embodiment, the nucleotide substitution is an A to G substitution. In an embodiment, the nucleotide substitution is a C to G substitution. In an embodiment, the nucleotide substitution is a G to U substitution. In an embodiment, the nucleotide substitution is G2C. In an embodiment, the nucleotide substitution is G12C. In an embodiment, the nucleotide substitution is C13U. In an embodiment, the nucleotide substitution is G22A. In an embodiment, the nucleotide substitution is C23G. In an embodiment, the nucleotide substitution is U28C. In an embodiment, the nucleotide substitution is A31C. In an embodiment, the nucleotide substitution is U39G. In an embodiment, WO 2024/216206 PCT/US2024/024492 the nucleotide substitution is U40C. In an embodiment, the nucleotide substitution is A42G. In an embodiment, the nucleotide substitution is A43G. In an embodiment, the nucleotide substitution is A44G. In an embodiment, the nucleotide substitution is G46A. In an embodiment, the nucleotide substitution is C49G. In an embodiment, the nucleotide substitution is G65U. In an embodiment, the nucleotide substitution is U71G. In an embodiment, the nucleotide substitution is C72U. In an embodiment, the TREM has the nucleotide sequence of SEQ ID NO: 1149. In an embodiment, the TREM having SEQ ID NO: 1149 comprises a non-naturally occurring modification. In an embodiment, the TREM having SEQ ID NO: 1149 has a non- naturally occurring modification listed in Table 6, e.g., one of Pattern Nos: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, and 32.A TREM may comprise a nucleotide substitution relative to the nucleotide sequence of SEQ ID NO: 734, wherein the nucleotide substitution is present in each of the [ASt Domainl] and the [ASt Domain2]. In an embodiment, the TREM comprises four nucleotide substitutions. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 1 and 10. In an embodiment, the nucleotide substitution is at a nucleotide position between positions and 70. In an embodiment, the nucleotide substitution is at nucleotide position 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In an embodiment, the nucleotide substitution is at nucleotide position 60, 61, 62, 63, 64, 64, 65, 66, 67, 68, 69, or 70. In an embodiment, the nucleotide substitution is at position 4. In an embodiment, the nucleotide substitution is at position 7. In an embodiment, the nucleotide substitution is at position 66. In an embodiment, the nucleotide substitution is at position 69. In an embodiment, the nucleotide substitution is a U to C substitution. In an embodiment, the nucleotide substitution is a G to A substitution. In an embodiment, the nucleotide substitution is a C to U substitution. In an embodiment, the nucleotide substitution is an A to G substitution. In an embodiment, the nucleotide substitution is U4C. In an embodiment, the nucleotide substitution is G7A. In an embodiment, the nucleotide substitution is C66U. In an embodiment, the nucleotide substitution is A69G. In an embodiment, the TREM has the nucleotide sequence of SEQ ID NO: 652. In an embodiment, the TREM having SEQ ID NO: 652 comprises a non- naturally occurring modification. In an embodiment, the TREM having SEQ ID NO: 652 has a non-naturally occurring modification listed in Table 6, e.g., one of Pattern Nos: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21,22, 23,24, 25,26, 27, 28, 29, 30, 31, and 32.

WO 2024/216206 PCT/US2024/024492 A TREM may comprise a nucleotide substitution relative to the nucleotide sequence of SEQ ID NO: 734, wherein the nucleotide substitution is present in the [ACH Domain], In an embodiment, the TREM comprises nine nucleotide substitutions. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 20 and 30. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 30 and 40. In an embodiment, the nucleotide substitution is at a nucleotide position between positions and 50. In an embodiment, the nucleotide substitution is at nucleotide position 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. In an embodiment, the nucleotide substitution is at nucleotide position 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40. In an embodiment, the nucleotide substitution is at nucleotide position 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50. In an embodiment, the nucleotide substitution is at position 27. In an embodiment, the nucleotide substitution is at position 28. In an embodiment, the nucleotide substitution is at position 29. In an embodiment, the nucleotide substitution is at position 31. In an embodiment, the nucleotide substitution is at position 39. In an embodiment, the nucleotide substitution is at position 40. In an embodiment, the nucleotide substitution is at position 41. In an embodiment, the nucleotide substitution is at position 42. In an embodiment, the nucleotide substitution is at position 43. In an embodiment, the nucleotide substitution is a U to A substitution. In an embodiment, the nucleotide substitution is a U to C substitution. In an embodiment, the nucleotide substitution is a G to C substitution. In an embodiment, the nucleotide substitution is an A to U substitution. In an embodiment, the nucleotide substitution is a C to G substitution. In an embodiment, the nucleotide substitution is an A to G substitution. In an embodiment, the nucleotide substitution is U27A. In an embodiment, the nucleotide substitution is U28C. In an embodiment, the nucleotide substitution is G29C. In an embodiment, the nucleotide substitution is A31U. In an embodiment, the nucleotide substitution is U39A. In an embodiment, the nucleotide substitution is U40C. In an embodiment, the nucleotide substitution is C41G. In an embodiment, the nucleotide substitution is A42G. In an embodiment, the nucleotide substitution is A43U. In an embodiment, the TREM has the nucleotide sequence of SEQ ID NO; 702. In an embodiment, the TREM having SEQ ID NO: 702 comprises a non-naturally occurring modification. In an embodiment, the TREM having SEQ ID NO: 702 has a non-naturally occurring modification listed in Table 6, e.g., one of Pattern Nos: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, and 32.

WO 2024/216206 PCT/US2024/024492 A TREM may comprise a nucleotide substitution relative to the nucleotide sequence of SEQ ID NO: 734, wherein the nucleotide substitution is present in each of the [ASt Domainl] and the [ASt Domain2]. In an embodiment, the TREM comprises eight nucleotide substitutions. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 1 and 10. In an embodiment, the nucleotide substitution is at a nucleotide position between positions and 70. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 70 and 80. In an embodiment, the nucleotide substitution is at nucleotide position 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In an embodiment, the nucleotide substitution is at nucleotide position 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70. In an embodiment, the nucleotide substitution is at nucleotide position 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80. In an embodiment, the nucleotide substitution is at position 1. In an embodiment, the nucleotide substitution is at position 2. In an embodiment, the nucleotide substitution is at position 4. In an embodiment, the nucleotide substitution is at position 5. In an embodiment, the nucleotide substitution is at position 68. In an embodiment, the nucleotide substitution is at position 69. In an embodiment, the nucleotide substitution is at position 71. In an embodiment, the nucleotide substitution is at position 72. In an embodiment, the nucleotide substitution is a G to A substitution. In an embodiment, the nucleotide substitution is a G to C substitution. In an embodiment, the nucleotide substitution is a U to A substitution. In an embodiment, the nucleotide substitution is a C to A substitution. In an embodiment, the nucleotide substitution is a G to U substitution. In an embodiment, the nucleotide substitution is an A to U substitution. In an embodiment, the nucleotide substitution is a U to G substitution. In an embodiment, the nucleotide substitution is a C to U substitution. In an embodiment, the nucleotide substitution is G1A. In an embodiment, the nucleotide substitution is G2C. In an embodiment, the nucleotide substitution is U4A. In an embodiment, the nucleotide substitution is C5A. In an embodiment, the nucleotide substitution is G68U. In an embodiment, the nucleotide substitution is A69U. In an embodiment, the nucleotide substitution is U71G. In an embodiment, the nucleotide substitution is C72U. In an embodiment, the TREM has the nucleotide sequence of SEQ ID NO; 627. In an embodiment, the TREM having SEQ ID NO: 627 comprises a non-naturally occurring modification. In an embodiment, the TREM having SEQ ID NO: 627 has a non-naturally occurring modification listed in Table 6, e.g., one of Pattern Nos: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, and 32.

WO 2024/216206 PCT/US2024/024492 A TREM may comprise a nucleotide substitution relative to the nucleotide sequence of SEQ ID NO: 734, wherein the nucleotide substitution is present in each of the [ASt Domainl], the [DH Domain], the [VL Domain], and the [ASt Domain2]. In an embodiment, the TREM comprises five nucleotide substitutions. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 1 and 10. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 20 and 30. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 40 and 50. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 60 and 70. In an embodiment, the nucleotide substitution is at nucleotide position 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In an embodiment, the nucleotide substitution is at nucleotide position 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. In an embodiment, the nucleotide substitution is at nucleotide position 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50. In an embodiment, the nucleotide substitution is at nucleotide position 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70. In an embodiment, the nucleotide substitution is at position 4. In an embodiment, the nucleotide substitution is at position 26. In an embodiment, the nucleotide substitution is at position 49. In an embodiment, the nucleotide substitution is at position 65. In an embodiment, the nucleotide substitution is at position 69. In an embodiment, the nucleotide substitution is a U to C substitution. In an embodiment, the nucleotide substitution is an A to G substitution. In an embodiment, the nucleotide substitution is a C to G substitution. In an embodiment, the nucleotide substitution is a G to C substitution. In an embodiment, the nucleotide substitution is U4C. In an embodiment, the nucleotide substitution is A26G. In an embodiment, the nucleotide substitution is C49G. In an embodiment, the nucleotide substitution is G65C. In an embodiment, the nucleotide substitution is A69G. In an embodiment, the TREM has the nucleotide sequence of SEQ ID NO: 1150. In an embodiment, the TREM having SEQ ID NO: 1150 comprises a non-naturally occurring modification. In an embodiment, the TREM having SEQ ID NO: 1150 has a non-naturally occurring modification listed in Table 6, e.g., one of Pattern Nos: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, and 32.A TREM may comprise a nucleotide substitution relative to the nucleotide sequence of SEQ ID NO: 734, wherein the nucleotide substitution is present in each of the [VL Domain] and the [ASt Domain2]. In an embodiment, the TREM comprises two nucleotide substitutions. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 40 and 50.

WO 2024/216206 PCT/US2024/024492 In an embodiment, the nucleotide substitution is at a nucleotide position between positions and 70. In an embodiment, the nucleotide substitution is at nucleotide position 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50. In an embodiment, the nucleotide substitution is at nucleotide position 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70. In an embodiment, the nucleotide substitution is at position 49. In an embodiment, the nucleotide substitution is at position 65. In an embodiment, the nucleotide substitution is a C to G substitution. In an embodiment, the nucleotide substitution is a Gto C substitution. In an embodiment, the nucleotide substitution is C49G. In an embodiment, the nucleotide substitution is G65C. In an embodiment, the TREM has the nucleotide sequence of SEQ ID NO: 1151. In an embodiment, the TREM having SEQ ID NO: 1151 comprises a non-naturally occurring modification. In an embodiment, the TREM having SEQ ID NO: 1151 has a non-naturally occurring modification listed in Table 6, e.g., one of Pattern Nos: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, and 32.A TREM may comprise a nucleotide substitution relative to the nucleotide sequence of SEQ ID NO: 734, wherein the nucleotide substitution is present in each of the [ASt Domainl] and the [ASt Domain2]. In an embodiment, the TREM comprises five nucleotide substitutions. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 1 and 10. In an embodiment, the nucleotide substitution is at a nucleotide position between positions and 70. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 70 and 80. In an embodiment, the nucleotide substitution is at nucleotide position 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In an embodiment, the nucleotide substitution is at nucleotide position 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70. In an embodiment, the nucleotide substitution is at nucleotide position 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80. In an embodiment, the nucleotide substitution is at position 1. In an embodiment, the nucleotide substitution is at position 2. In an embodiment, the nucleotide substitution is at position 4. In an embodiment, the nucleotide substitution is at position 69. In an embodiment, the nucleotide substitution is at position 72. In an embodiment, the nucleotide substitution is a G to U substitution. In an embodiment, the nucleotide substitution is a Gto A substitution. In an embodiment, the nucleotide substitution is a U to A substitution. In an embodiment, the nucleotide substitution is an A to U substitution. In an embodiment, the nucleotide substitution is a C to A substitution. In an embodiment, the nucleotide substitution is G1U. In an embodiment, the nucleotide substitution is G2A. In an WO 2024/216206 PCT/US2024/024492 embodiment, the nucleotide substitution is U4A. In an embodiment, the nucleotide substitution is A69U. In an embodiment, the nucleotide substitution is C72A. In an embodiment, the TREM has the nucleotide sequence of SEQ ID NO: 794. In an embodiment, the TREM having SEQ ID NO: 794 comprises a non-naturally occurring modification. In an embodiment, the TREM having SEQ ID NO: 794 has a non-naturally occurring modification listed in Table 6, e.g., one of Pattern Nos: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21,22, 23,24, 25, 26, 27, 28, 29, 30, 31, and 32.A TREM may comprise a nucleotide substitution relative to the nucleotide sequence of SEQ ID NO: 734, wherein the nucleotide substitution is present in each of the [ASt Domainl], the [ACH Domain], and the [ASt Domain2]. In an embodiment, the TREM comprises four nucleotide substitutions. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 1 and 10. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 20 and 30. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 40 and 50. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 70 and 80. In an embodiment, the nucleotide substitution is at nucleotide position 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In an embodiment, the nucleotide substitution is at nucleotide position 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. In an embodiment, the nucleotide substitution is at nucleotide position 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50. In an embodiment, the nucleotide substitution is at nucleotide position 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80. In an embodiment, the nucleotide substitution is at position 2. In an embodiment, the nucleotide substitution is at position 27. In an embodiment, the nucleotide substitution is at position 43. In an embodiment, the nucleotide substitution is at position 71. In an embodiment, the nucleotide substitution is a Gto C substitution. In an embodiment, the nucleotide substitution is a U to G substitution. In an embodiment, the nucleotide substitution is an A to C substitution. In an embodiment, the nucleotide substitution is G2C. In an embodiment, the nucleotide substitution is U27G. In an embodiment, the nucleotide substitution is A43C. In an embodiment, the nucleotide substitution is U71G. In an embodiment, the TREM has the nucleotide sequence of SEQ ID NO: 641. In an embodiment, the TREM having SEQ ID NO: 6comprises a non-naturally occurring modification. In an embodiment, the TREM having SEQ ID NO: 641 has a non-naturally occurring modification listed in Table 6, e.g., one of Pattern Nos: 1, WO 2024/216206 PCT/US2024/024492 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, and 32.A TREM may comprise a nucleotide substitution relative to the nucleotide sequence of SEQ ID NO: 734, wherein the nucleotide substitution is present in the [ACH Domain], In an embodiment, the TREM comprises four nucleotide substitutions. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 20 and 30. In an embodiment, the nucleotide substitution is at a nucleotide position between positions 30 and 40. In an embodiment, the nucleotide substitution is at a nucleotide position between positions and 50. In an embodiment, the nucleotide substitution is at nucleotide position 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30. In an embodiment, the nucleotide substitution is at nucleotide position 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40. In an embodiment, the nucleotide substitution is at nucleotide position 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50. In an embodiment, the nucleotide substitution is at position 28. In an embodiment, the nucleotide substitution is at position 31. In an embodiment, the nucleotide substitution is at position 39. In an embodiment, the nucleotide substitution is at position 42. In an embodiment, the nucleotide substitution is a U to C substitution. In an embodiment, the nucleotide substitution is an A to U substitution. In an embodiment, the nucleotide substitution is a U to A substitution. In an embodiment, the nucleotide substitution is an A to G substitution. In an embodiment, the nucleotide substitution is U28C. In an embodiment, the nucleotide substitution is A31U. In an embodiment, the nucleotide substitution is U39A. In an embodiment, the nucleotide substitution is A42G. In an embodiment, the TREM has the nucleotide sequence of SEQ ID NO: 710. In an embodiment, the TREM having SEQ ID NO: 710 comprises a non-naturally occurring modification. In an embodiment, the TREM having SEQ ID NO: 710 has a non-naturally occurring modification listed in Table 6, e.g., one of Pattern Nos: 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31, and 32. Table7: Exemplary TREM sequences Scaffold No. SEQ ID NO.

Substitutions Relative to SEQ ID NO: 734 Nucleotide Mutation Pattern743 1 A44G639 8 G2C, U4C, C5G, C6A, G67U, G68C, A69G, U71G WO 2024/216206 PCT/US2024/024492 3 1149 17G2C, G12C, C13U, G22A, C23G, U28C, A31C, U39G, U40C, A42G, A43G, A44G, G46A, C49G, G65U, U71G, C72U652 4 U4C, G7A, C66U, A69G702 9U27A, U28C, G29C, A31U, U39A, U40C, C41G,A42G, A43U627 8 GIA, G2C, U4A, C5A, G68U, A69U, U71G, C72U1150 5 U4C, A26G, C49G, G65C, A69G1151 2 C49G, G65C794 5 G1U, G2A, U4A, A69U, C72A641 4 G2C, U27G, A43C, U71G710 4 U28C, A31U, U39A, A42G734 0 Reference sequence.

In an embodiment, a TREM may comprise a nucleotide sequence scaffold, e.g., any one of Scaffold Nos: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12. In an embodiment, a TREM may comprise a chemical modification pattern, e.g., any one of Pattern Nos: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21,22, 23,24, 25,26, 27, 28, 29, 30, 31, and 32. In an embodiment, a TREM may comprise a nucleotide sequence scaffold, e.g., any one of Scaffold Nos: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12, and a chemical modification pattern, e.g., any one of Pattern Nos: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, and 32. In an embodiment, a functional parameter of a TREM may be modulated by the sequence scaffold. In an embodiment, a functional parameter of a TREM may be modulated by the chemical modification pattern. In an embodiment, a functional parameter of a TREM may be modulated by both the sequence scaffold and the modification pattern. In an embodiment, the functional parameter of the TREM that is modulated by the nucleotide sequence scaffold, the chemical modification pattern, or both the nucleotide sequence scaffold and the chemical modification pattern is the 10g2 activity of the TREM relative to mock, e.g., 10g2 activity of the TREM as provided in FIG. 1. In an embodiment, the 10g2 activity of a TREM can be modulated to be between 1 and 1024. In an embodiment, the 10g2 activity of a TREM can be modulated to be between 1-4, 4-16, 16-64, 64-256, or 256-1024. In an embodiment, the logactivity of a TREM can be modulated to be between about 1 to about 40. In an embodiment, the log2 activity of a TREM can be modulated to be between about 2 to about 60. In an embodiment, the log2 activity of a TREM can be modulated to be between about 3 to about 60. In an embodiment, the 10g2 activity of a TREM can be modulated to be between about 3 to about 50.

WO 2024/216206 PCT/US2024/024492 In an embodiment, the 10g2 activity of a TREM can be modulated to be between about 2 to about 128. In an embodiment, the 10g2 activity of a TREM can be modulated to be between about 3 to about 30. In an embodiment, the 10g2 activity of a TREM can be modulated to be between about to about 512. In an embodiment, the 10g2 activity of a TREM can be modulated to be between about 4 to about 15. In an embodiment, the log2 activity of a TREM can be modulated to be between about 8 to about 100. In an embodiment, the 10g2 activity of a TREM can be modulated to be between about 3 to about 70. In an embodiment, the log2 activity of a TREM can be modulated to be between about 3 to about 512. In an embodiment, the 10g2 activity of a TREM can be modulated to be between about 3 to about 128. In an embodiment, the 10g2 activity of a TREM can be modulated to be between about 3 to about 70. In an embodiment, the log2 activity of a TREM can be modulated to be between about 4 to about 128. In an embodiment, the 10gactivity of a TREM can be modulated to be between about 32 to about 256. In an embodiment, the log2 activity of a TREM can be modulated to be between about 30 to about 512. In an embodiment, the 10g2 activity of a TREM can be modulated to be between about 60 to about 512. In an embodiment, the 10g2 activity of a TREM can be modulated to be between about 32 to about 512. In an embodiment, the 10g2 activity of a TREM can be modulated to be between about 64 to about 512. In an embodiment, the 10g2 activity of a TREM can be modulated to be between about 8 to about 256. In an embodiment, the 10g2 activity of a TREM can be modulated to be between about 10 to about 256. In an embodiment, the 10g2 activity of a TREM can be modulated to be between about 10 to about 400. In an embodiment, the 10g2 activity of a TREM can be modulated to be between about 64 to about 500. In an embodiment, the 10g2 activity of a TREM can be modulated to be between about 128 to about 800. In an embodiment, the 10gactivity of a TREM can be modulated to be between about 14 to about 400. In an embodiment, the log2 activity of a TREM can be modulated to be between about 128 to about 700. In an embodiment, the 10g2 activity of a TREM can be modulated to be between about 8 to about 300. In an embodiment, the 10g2 activity of a TREM can be modulated to be between about 40 to about 512. In an embodiment, the 10g2 activity of a TREM can be modulated to be between about 100 to about 512. In an embodiment, the 10g2 activity of a TREM can be modulated to be between about 128 to about 400. In an embodiment, the log2 activity of a TREM can be modulated to be between about 64 to about 512. In an embodiment, the 10g2 activity of a TREM can be modulated to be between about 200 to about 512. In an embodiment, the log2 activity of a WO 2024/216206 PCT/US2024/024492 TREM can be modulated by Pattern No: 1 to be between about 1 to about 40. In an embodiment, the log2 activity of a TREM can be modulated by Pattern No: 2 to be between about 2 to about 60. In an embodiment, the 10g2 activity of a TREM can be modulated by Pattern No: 3 to be between about 3 to about 60. In an embodiment, the log2 activity of a TREM can be modulated by Pattern No: 4 to be between about 3 to about 50. In an embodiment, the 10g2 activity of a TREM can be modulated by Pattern No: 5 to be between about 2 to about 128. In an embodiment, the 10g2 activity of a TREM can be modulated by Pattern No: 6 to be between about 3 to about 30. In an embodiment, the log2 activity of a TREM can be modulated by Pattern No: 7 to be between about 3 to about 512. In an embodiment, the 10g2 activity of a TREM can be modulated by Pattern No: 8 to be between about 4 to about 15. In an embodiment, the 10gactivity of a TREM can be modulated by Pattern No: 9 to be between about 8 to about 100. In an embodiment, the 10g2 activity of a TREM can be modulated by Pattern No: 10 to be between about 3 to about 70. In an embodiment, the log2 activity of a TREM can be modulated by Pattern No: 11 to be between about 3 to about 512. In an embodiment, the 10g2 activity of a TREM can be modulated by Pattern No: 12 to be between about 3 to about 128. In an embodiment, the 10gactivity of a TREM can be modulated by Pattern No: 13 to be between about 3 to about 70. In an embodiment, the 10g2 activity of a TREM can be modulated by Pattern No: 14 to be between about 4 to about 128. In an embodiment, the 10g2 activity of a TREM can be modulated by Pattern No: 15 to be between about 32 to about 256. In an embodiment, the 10g2 activity of a TREM can be modulated by Pattern No: 16 to be between about 30 to about 512. In an embodiment, the 10g2 activity of a TREM can be modulated by Pattern No: 17 to be between about 60 to about 512. In an embodiment, the 10g2 activity of a TREM can be modulated by Pattern No: 18 to be between about 32 to about 512. In an embodiment, the 10g2 activity of a TREM can be modulated by Pattern No: 19 to be between about 64 to about 512. In an embodiment, the 10g2 activity of a TREM can be modulated by Pattern No: 20 to be between about 8 to about 256. In an embodiment, the 10g2 activity of a TREM can be modulated by Pattern No: 21 to be between about 10 to about 256. In an embodiment, the 10g2 activity of a TREM can be modulated by Pattern No: 22 to be between about 10 to about 400. In an embodiment, the 10g2 activity of a TREM can be modulated by Pattern No: 23 to be between about 64 to about 500. In an embodiment, the 10g2 activity of a TREM can be modulated by Pattern No: 24 to be between about 128 to about 800. In an embodiment, the 10g2 activity of a WO 2024/216206 PCT/US2024/024492 TREM can be modulated by Pattern No: 25 to be between about 14 to about 400. In an embodiment, the 10g2 activity of a TREM can be modulated by Pattern No: 26 to be between about 128 to about 700. In an embodiment, the 10g2 activity of a TREM can be modulated by Pattern No: 27 to be between about 8 to about 300. In an embodiment, the log2 activity of a TREM can be modulated by Pattern No: 28 to be between about 40 to about 512. In an embodiment, the 10g2 activity of a TREM can be modulated by Pattern No: 29 to be between about 100 to about 512. In an embodiment, the log2 activity of a TREM can be modulated by Pattern No: 30 to be between about 128 to about 400. In an embodiment, the 10g2 activity of a TREM can be modulated by Pattern No: 31 to be between about 64 to about 512. In an embodiment, the 10g2 activity of a TREM can be modulated by Pattern No: 32 to be between about 200 to about 512. In an embodiment, the 10g2 activity of a TREM can be modulated by Scaffold No: 1 to be between about 1 to about 800. In an embodiment, the log2 activity of a TREM can be modulated by Scaffold No: 2 to be between about 4 to about 400. In an embodiment, the 10g2 activity of a TREM can be modulated by Scaffold No: 3 to be between about 3 to about 512. In an embodiment, the 10g2 activity of a TREM can be modulated by Scaffold No: 4 to be between about 3 to about 400. In an embodiment, the log2 activity of a TREM can be modulated by Scaffold No: 5 to be between about 3 to about 512. In an embodiment, the 10g2 activity of a TREM can be modulated by Scaffold No: 6 to be between about 2 to about 256. In an embodiment, the 10g2 activity of a TREM can be modulated by Scaffold No: 7 to be between about 3 to about 700. In an embodiment, the log2 activity of a TREM can be modulated by Scaffold No: 8 to be between about 2 to about 600. In an embodiment, the 10g2 activity of a TREM can be modulated by Scaffold No: 9 to be between about 3 to about 200. In an embodiment, the 10g2 activity of a TREM can be modulated by Scaffold No: 10 to be between about 3 to about 800. In an embodiment, the 10g2 activity of a TREM can be modulated by Scaffold No: 11 to be between about 3 to about 300. In an embodiment, the 10g2 activity of a TREM can be modulated by Scaffold No: 12 to be between about 1 to about 400.In an embodiment, a TREM may comprise a nucleotide sequence scaffold, e.g., any one of Scaffold Nos: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12. In an embodiment, a TREM may comprise non-naturally occurring modifications, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, WO 2024/216206 PCT/US2024/024492 41, or more non-naturally occurring modifications. In an embodiment, a TREM may comprise a nucleotide sequence scaffold, e g., any one of Scaffold Nos: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12, and non-naturally occurring modifications, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, or more non-naturally occurring modifications. In an embodiment, a functional parameter of a TREM may be modulated by the sequence scaffold. In an embodiment, a functional parameter of a TREM may be modulated by the number of non-naturally occurring modifications. In an embodiment, a functional parameter of a TREM may be modulated by both the sequence scaffold and the number of non-naturally occurring modifications. In an embodiment, the functional parameter of the TREM that is modulated by the nucleotide sequence scaffold, the number of non-naturally occurring modifications, or both the nucleotide sequence scaffold and the number of non-naturally occurring modifications is the 10g2 activity of the TREM relative to mock, e.g., 10g2 activity of the TREM as provided in FIG. 2. In an embodiment, the 10g2 activity of a TREM can be modulated by zero non-naturally occurring modifications to be between about and about 256. In an embodiment, the log2 activity of a TREM can be modulated by four non-naturally occurring modifications to be between about 128 and about 800. In an embodiment, the 10g2 activity of a TREM can be modulated by five non-naturally occurring modifications to be between about 256 and about 600. In an embodiment, the 10g2 activity of a TREM can be modulated by six non-naturally occurring modifications to be between about 2and about 512. In an embodiment, the log2 activity of a TREM can be modulated by eight non- naturally occurring modifications to be between about 150 and about 700. In an embodiment, the 10g2 activity of a TREM can be modulated by ten non-naturally occurring modifications to be between about 3 and about 100. In an embodiment, the 10g2 activity of a TREM can be modulated by thirteen non-naturally occurring modifications to be between about 3 and about 100. In an embodiment, the 10g2 activity of a TREM can be modulated by fourteen non-naturally occurring modifications to be between about 8 and about 400. In an embodiment, the logactivity of a TREM can be modulated by fifteen non-naturally occurring modifications to be between about 32 and about 250. In an embodiment, the 10g2 activity of a TREM can be modulated by sixteen non-naturally occurring modifications to be between about 8 and about 400. In an embodiment, the 10g2 activity of a TREM can be modulated by nineteen non-naturally occurring modifications to be between about 60 and about 400. In an embodiment, the 10g WO 2024/216206 PCT/US2024/024492 activity of a TREM can be modulated by twenty-one non-naturally occurring modifications to be between about 3 and about 128. In an embodiment, the 10g2 activity of a TREM can be modulated by twenty-two non-naturally occurring modifications to be between about 8 and about 256. In an embodiment, the 10g2 activity of a TREM can be modulated by twenty-four non- naturally occurring modifications to be between about 12 and about 500. In an embodiment, the 10g2 activity of a TREM can be modulated by twenty-five non-naturally occurring modifications to be between about 2 and about 60. In an embodiment, the log2 activity of a TREM can be modulated by twenty-six non-naturally occurring modifications to be between about 3 and about 55. In an embodiment, the 10g2 activity of a TREM can be modulated by twenty-seven non- naturally occurring modifications to be between about 60 and about 500. In an embodiment, the 10g2 activity of a TREM can be modulated by twenty-eight non-naturally occurring modifications to be between about 2 and about 100. In an embodiment, the 10g2 activity of a TREM can be modulated by twenty-nine non-naturally occurring modifications to be between about 55 and about 600. In an embodiment, the 10g2 activity of a TREM can be modulated by thirty non-naturally occurring modifications to be between about 4 and about 128. In an embodiment, the 10g2 activity of a TREM can be modulated by thirty-one non-naturally occurring modifications to be between about 1 and about 32. In an embodiment, the 10g2 activity of a TREM can be modulated by thirty-two non-naturally occurring modifications to be between about 3 and about 128. In an embodiment, the 10g2 activity of a TREM can be modulated by thirty-three non-naturally occurring modifications to be between about 64 and about 512. In an embodiment, the 10g2 activity of a TREM can be modulated by thirty-four non-naturally occurring modifications to be between about 32 and about 512. In an embodiment, the 10gactivity of a TREM can be modulated by thirty-five non-naturally occurring modifications to be between about 20 and about 512. In an embodiment, the log2 activity of a TREM can be modulated by thirty-six non-naturally occurring modifications to be between about 2 and about 512. In an embodiment, the 10g2 activity of a TREM can be modulated by thirty-seven non- naturally occurring modifications to be between about 3 and about 512. In an embodiment, the 10g2 activity of a TREM can be modulated by forty non-naturally occurring modifications to be between about 100 and about 512. In an embodiment, the log2 activity of a TREM can be modulated by forty-one non-naturally occurring modifications to be between about 6 and about 256. In an embodiment, the 10g2 activity of a TREM can be modulated by Scaffold No: 1 to be WO 2024/216206 PCT/US2024/024492 between about 1 to about 400. In an embodiment, the 10g2 activity of a TREM can be modulated by Scaffold No: 2 to be between about 4 to about 512. In an embodiment, the 10g2 activity of a TREM can be modulated by Scaffold No: 3 to be between about 4 to about 512. In an embodiment, the 10g2 activity of a TREM can be modulated by Scaffold No: 4 to be between about 3 to about 400. In an embodiment, the 10g2 activity of a TREM can be modulated by Scaffold No: 5 to be between about 3 to about 700. In an embodiment, the 10g2 activity of a TREM can be modulated by Scaffold No: 6 to be between about 3 to about 256. In an embodiment, the 10g2 activity of a TREM can be modulated by Scaffold No: 7 to be between about 3 to about 800. In an embodiment, the 10g2 activity of a TREM can be modulated by Scaffold No: 8 to be between about 2 to about 600. In an embodiment, the log2 activity of a TREM can be modulated by Scaffold No: 9 to be between about 3 to about 256. In an embodiment, the 10g2 activity of a TREM can be modulated by Scaffold No: 10 to be between about 3 to about 800. In an embodiment, the 10g2 activity of a TREM can be modulated by Scaffold No: 11 to be between about 3 to about 500. In an embodiment, the 10g2 activity of a TREM can be modulated by Scaffold No: 12 to be between about 1 to about 256.In an embodiment, the TREM is not a TREM provided in FIG. 3. In an embodiment, the TREM does not have the nucleotide sequence of a TREM provided in FIG. 3. In an embodiment, the TREM does not comprise the nucleotide sequence of SEQ ID NO: 743. In an embodiment, the TREM does not comprise the nucleotide sequence of SEQ ID NO: 652. In an embodiment, the TREM does not comprise the nucleotide sequence of SEQ ID NO: 702. In an embodiment, the TREM does not comprise the nucleotide sequence of SEQ ID NO: 627. In an embodiment, the TREM does not comprise the nucleotide sequence of SEQ ID NO: 1150. In an embodiment, the TREM does not comprise the nucleotide sequence of SEQ ID NO: 1151. In an embodiment, the TREM does not comprise the nucleotide sequence of SEQ ID NO: 794. In an embodiment, the TREM does not comprise the nucleotide sequence of SEQ ID NO: 641. In an embodiment, the TREM does not comprise the nucleotide sequence of SEQ ID NO: 710.In an embodiment, the TREM does not comprise a pattern of non-naturally occurring modifications according to a pattern in Table 6 (e.g., a pattern selected from Pattern Nos. 1-32). In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No. 1 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No. 2 in 100 WO 2024/216206 PCT/US2024/024492 Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No. 3 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No. 4 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No. 5 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No. 6 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No. 7 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No. 8 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No. 9 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No. 10 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No. 11 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No. 12 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No. 13 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No. 14 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No. 15 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No. 16 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No. 17 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No. 18 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No. 19 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No. 20 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No. 21 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No. 22 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring 101 WO 2024/216206 PCT/US2024/024492 modifications according to Pattern No. 23 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No. 24 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No. 25 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No. 26 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No. 27 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No. 28 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No. 29 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No. 30 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No. 31 in Table 6. In an embodiment, the TREM does not comprise the pattern of non-naturally occurring modifications according to Pattern No. 32 in Table 6.In an embodiment, a TREM comprises a nucleotide sequence, e g., any one of the sequences provided in FIGs. 3 or 23. In an embodiment, a functional parameter of a TREM is modulated by a nucleotide substitution, e.g., a nucleotide substitution relative to a reference TREM sequence. In an embodiment, the functional parameter of the TREM that is modulated by a nucleotide substitution is the premature termination codon (PTC) read-through activity of the TREM, e.g., the ability of a TREM to decode a premature termination codon and continue translation within the coding sequence of a protein. For example, a nucleotide substitution may modulate the relative abundance of a TREM in a pool of hits resulting from a screen of a library of TREMs comprising nucleotide substitutions for PTC readthrough activity. In an embodiment, a nucleotide substitution at a given position in a TREM sequence increases the hit abundance of TREMs comprising said nucleotide substitution relative to a TREM library composition.In an embodiment, a TREM comprises a nucleotide substitution in a particular region of the TREM. In an embodiment, the nucleotide substitution in a particular region of a TREM modulates a functional parameter of the TREM, e.g., the activity or stability of the TREM. In an embodiment, a nucleotide substitution in a particular region of a TREM modulates activity, e.g., PTC read-through activity, of a TREM. For example, a nucleotide substitution in a particular 102 WO 2024/216206 PCT/US2024/024492 region of a TREM may increase activity of the TREM and a nucleotide substitution in a second region of a TREM may decrease activity of the TREM. In an embodiment, the activity that is modulated by the nucleotide substitution is the PTC read-through activity of the TREM, e.g., the ability of the TREM to support translation of a premature termination codon (PTC) in a protein coding sequence. In an embodiment, the PTC read-through activity of a TREM modulates the abundance of the TREM in a pool of hits resulting from a pooled screen of a plurality of TREMs comprising nucleotide substitutions. In an embodiment, a TREM having increased PTC read- through activity has greater abundance, e.g., relative to a reference standard, in a pool of hits resulting from a pooled screen of TREMs comprising nucleotide substitutions. In an embodiment, a TREM having decreased PTC read-through activity has lesser abundance, e.g., relative to a reference standard, in a pool of hits resulting from a pooled screen of TREMs comprising nucleotide substitutions. In an embodiment, a nucleotide substitution in a particular region of a TREM modulates the abundance of the TREM in a pool of hits resulting from a pooled screen for PTC read-through activity. In an embodiment, a nucleotide substitution in a particular region of a TREM increases the abundance of the TREM in a pool of hits resulting from a pooled screen. In an embodiment, a nucleotide substitution in the stem, e.g., base-paired region, formed between the [ASt Domainl] and the [ASt Domain2], e.g., the stem formed between positions 1-7 and 66-72, increases the abundance of a TREM in a pool of hits resulting from a pooled screen. In an embodiment, a nucleotide substitution in the stem formed between base pairs at positions 1 and 72, 2 and 71,3 and 70, 4 and 69, 5 and 68, 6 and 67, and 7 and increases the abundance of a TREM in a pool of hits resulting from a pooled screen, e.g., as shown in FIG. 4A. In an embodiment, a nucleotide substitution in the stem of the [ACH Domain], e.g., the stem formed between positions 27-31 and 39-43, increases the abundance of a TREM in a pool of hits resulting from a pooled screen. In an embodiment, a nucleotide substitution in the stem formed between base pairs at positions 27 and 43, 28 and 42, 29 and 41, and 40, and 31 and 39 increases the abundance of a TREM in a pool of hits resulting from a pooled screen, e.g., as shown in FIG. 4A. In an embodiment, a nucleotide substitution in a particular region of a TREM decreases the abundance of a TREM in a pool of hits resulting from a pooled screen. In an embodiment, a nucleotide substitution in the loop region of the [ACH Domain], e.g., positions 32-38 decreases the abundance of a TREM in a pool of hits resulting from a pooled screen. In an embodiment, a nucleotide substitution in the loop formed at positions 103 WO 2024/216206 PCT/US2024/024492 32, 33, 34, 35, 36, 37, and 38 decreases the abundance of a TREM in a pool of hits resulting from a pooled screen, e.g., as shown in FIG. 4A. In an embodiment, a nucleotide substitution in a particular region of a TREM modulates the abundance of various TREM scaffolds, e.g., TREMs specific to various amino acids, e.g., TREMs having the ability to be charged with various amino acids, in a pool of hits resulting from a pooled screen. In an embodiment, a nucleotide substitution in a particular position of a TREM increases the abundance of certain TREM scaffolds in a pool of hits resulting from a pooled screen, e.g., nucleotide substitutions in the base-pair formed between positions 51 and 63. In an embodiment, a nucleotide substitution in the base pair formed between positions 51 and 63 increases the abundance of certain TREM scaffolds in a pool of hits resulting from a pooled screen, e.g., as shown in FIG. 4A.In an embodiment, the abundance of a nucleotide substitution at a particular position in a TREM in a pool of hits resulting from a pooled screen is modulated by the activity of the TREM, e.g., the PTC read-through activity of the TREM. In an embodiment, the normalized abundance of a nucleotide substitution in a pool of hits is about 0 and about 4.5, e.g., as provided in FIG. 4B. In an embodiment, the normalized abundance of a nucleotide substitution in a pool of hits is about 0 and about 3.5. In an embodiment, the normalized abundance of a nucleotide substitution in a pool of hits is about 0 and about 2.5. In an embodiment, the normalized abundance of a nucleotide substitution in a pool of hits is about 0 and about 2.In an embodiment, the enrichment, e.g., abundance, of a nucleotide substitution at a particular position in a TREM in a pool of hits resulting from a pooled screen is modulated by the activity of the TREM, e.g., the PTC read-through activity of the TREM. In an embodiment, a nucleotide substitution at a particular position in a TREM is enriched in a pool of hits resulting from a pooled screen, e.g., is more abundant in the pool of hits than the starting pool composition. In an embodiment, a nucleotide substitution at a particular position in a TREM is depleted in a pool of hits resulting from a pooled screen, e.g., is more abundant in the pool of hits than the starting pool composition. In an embodiment, a nucleotide substitution at a particular position in a TREM is enriched to be between about 0 and about 4, e.g., as provided in FIG. 5. In an embodiment, a nucleotide substitution at any of positions 1, 2, 3, 4, 5, 6, 7, 16, 17, 20a, 27, 28, 29, 30, 31, 39, 40, 41, 42, 43, 51, 59, 60, 63, 66, 67, 68, 69, 70, 71, 72, or 73 increases the abundance of a TREM in a pool of hits resulting from a pooled screen, e.g., as provided in FIG. 5. In an embodiment, a nucleotide substitution at any of positions 1, 2, 3, 4, 5, 6, 7, 16, 17, 20a, 104 WO 2024/216206 PCT/US2024/024492 27, 28, 29, 30, 31, 39, 40, 41, 42, 43, 51, 59, 60, 63, 66, 67, 68, 69, 70, 71, 72, or 73 increases premature termination codon (PTC) read-through activity of a TREM, e.g., as provided in FIG.5. In an embodiment, the activity of a TREM corresponding to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1835, 1867, 2000, 2001,2016, 2017, 2022, 2023, 2020, 2021, 2018, 2019, 1654, or 1660, e.g., the PTC read-through activity of a TREM, is increased by a nucleotide substitution at any of positions 1, 2, 3, 4, 5, 6, or 7, e.g., within the [ASt Domainl], e.g., as shown in FIG. 5. In an embodiment, the activity of a TREM corresponding to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1835, 1867, 2000, 2001, 2016, 2017, 2022, 2023, 2020, 2021, 2018, 2019, 1654, or 1660, e.g., the PTC read-through activity of a TREM, is increased by a nucleotide substitution at any of positions or 17, e.g., within the [DH Domain], e.g., as shown in FIG. 5. In an embodiment, the activity of a TREM corresponding to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1835, 1867, 2000, 2001, 2016, 2017, 2022, 2023, 2020, 2021, 2018, 2019, 1654, or 1660, e.g., the PTC read-through activity of a TREM, is increased by a nucleotide substitution at position 20a, e.g., within the [DH Domain], e.g., as shown in FIG. 5. In an embodiment, the activity of a TREM corresponding to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1835, 1867, 2000, 2001,2016, 2017, 2022, 2023,2020, 2021,2018, 2019, 1654, or 1660, e.g., the PTC read-through activity of a TREM, is increased by a nucleotide substitution at any of positions 27, 28, 29, 30, or 31, e.g., within the [ACH Domain], e.g., as shown in FIG. 5. In an embodiment, the activity of a TREM corresponding to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1835, 1867, 2000, 2001,2016, 2017, 2022, 2023,2020, 2021, 2018, 2019, 1654, or 1660, e.g., the PTC read-through activity of a TREM, is increased by a nucleotide substitution at any of positions 39, 40, 41, 42, or 43, e.g., within the [ACH Domain], e.g., as shown in FIG. 5. In an embodiment, the activity of a TREM corresponding to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1835, 1867, 2000, 2001, 2016, 2017, 2022, 2023, 2020, 2021, 2018, 2019, 1654, or 1660, e.g., the PTC read-through activity of a TREM, is increased by a nucleotide substitution at position 51, e.g., within the [TH Domain], e.g., as shown in FIG. 5. In an embodiment, the activity of a TREM corresponding to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1835, 1867, 2000, 2001, 2016, 2017, 2022, 2023, 2020, 2021, 2018, 2019, 1654, or 1660, e.g., the PTC read-through activity of a TREM, is increased by a nucleotide substitution at any of positions 59 or 60, e.g., within the 105 WO 2024/216206 PCT/US2024/024492 [TH Domain], e.g., as shown in FIG. 5. In an embodiment, the activity of a TREM corresponding to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1835, 1867, 2000, 2001, 2016, 2017, 2022, 2023, 2020, 2021, 2018, 2019, 1654, or 1660, e.g., the PTC read-through activity of a TREM, is increased by a nucleotide substitution at position 63, e.g., within the [TH Domain], e.g., as shown in FIG. 5. In an embodiment, the activity of a TREM corresponding to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1835, 1867, 2000, 2001, 2016, 2017, 2022, 2023, 2020, 2021, 2018, 2019, 1654, or 1660, e.g., the PTC read-through activity of a TREM, is increased by a nucleotide substitution at any of positions 66, 67, 68, 69, 70, 71, 72, or 73, e.g., within the [ASt Domain2], e.g., as shown in FIG. 5. In an embodiment, the activity of a TREM corresponding to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs; 1638, 1835, 1867, 2000, 2001,2016, 2017, 2022, 2023,2020, 2021, 2018, 2019, 1654, or 1660, e.g., the PTC read-through activity of a TREM, is decreased by a nucleotide substitution at any of positions 32, 33, 34, 35, 36, 37, or 38, e.g., within the [ACH Domain], e.g., as shown in FIG. 5.In an embodiment, the abundance of a nucleotide substitution at a particular position in a TREM in a pool of hits resulting from a pooled screen is modulated by the activity of the TREM, e.g., the PTC read-through activity of the TREM. In an embodiment, the normalized abundance of a nucleotide substitution in a pool of hits is about 0 and about 3.6, e.g., as provided in FIG. 6. In an embodiment, the normalized abundance of a nucleotide substitution in a pool of hits is about 0 and about 8, e.g., as provided in FIG. 7. In an embodiment, the normalized abundance of a nucleotide substitution in a pool of hits is about 0 and about 3.5, e.g., as provided in FIG. 8. In an embodiment, the normalized abundance of a nucleotide substitution in a pool of hits is about and about 5, e.g., as provided in FIG. 9. In an embodiment, the normalized abundance of a nucleotide substitution in a pool of hits is about 0 and about 5, e.g., as provided in FIG. 10. In an embodiment, the normalized abundance of a nucleotide substitution in a pool of hits is about and about 12, e.g., as provided in FIG. 11.In an embodiment, the normalized abundance of a nucleotide substitution in a pool of hits is about 0 and about 2.1, e.g., as provided in FIG. 12. In an embodiment, the normalized abundance of a nucleotide substitution in a pool of hits is about and about 2.4, e.g., as provided in FIG. 13. In an embodiment, the normalized abundance of a nucleotide substitution in a pool of hits is about 0 and about 4, e.g., as provided in FIG. 14. In an 106 WO 2024/216206 PCT/US2024/024492 embodiment, the normalized abundance of a nucleotide substitution in a pool of hits is about and about 4.5, e.g., as provided in FIG. 15.In an embodiment, the enrichment, e.g., abundance, of a nucleotide substitution at a particular position in a TREM in a pool of hits resulting from a pooled screen is modulated by the activity of the TREM, e.g., the PTC read-through activity of the TREM. In an embodiment, the nucleotide substitution disrupts base-pairing at a particular position in a TREM. In an embodiment, a nucleotide substitution that disrupts base-pairing is enriched in a pool of hits resulting from a pooled screen. In an embodiment, a nucleotide substitution that disrupts base- pairing is depleted in a pool of hits resulting from a pooled screen. In an embodiment, a nucleotide substitution that disrupts base-pairing is enriched to be about 0 toa bout 4, e.g., as provided in FIG. 16.In an embodiment, the enrichment of a TREM comprising a nucleotide substitution in a pool of hits, e.g., a pool of TREMs having increased activity, e.g., increased PTC read-through activity, is reproducible between replicate screens, e.g., as shown in FIGs. 17 and 19A-B.In an embodiment, the 10g2 PTC read-through activity of a TREM comprising a nucleotide substitution, e.g., relative to a parent TREM sequence, e.g., starting TREM sequence, is modulated by the nucleotide substitution. In an embodiment, the 10g2 PTC read-through activity of a TREM is modulated by a nucleotide substitution to be between about -0.5 to about 6.8, e.g., as provided in FIG. 18. In an embodiment, the 10g2 PTC read-through activity of a TREM is modulated by a nucleotide substitution to be between about -0.5 to about 4 at a low TREM dose. In an embodiment, the log2 PTC read-through activity of a TREM is modulated by a nucleotide substitution to be between about 0.5 to about 6.8 at a high TREM dose.In an embodiment, delivery of a TREM comprising a nucleotide substitution does not affect the activity of the TREM, e.g., the PTC read-through activity of the TREM. In an embodiment, the PTC read-through activity of a TREM delivered as a synthesized oligonucleotide or by lentivirus is about equivalent, e.g., as provided in FIG. 22 and FIG. 25. In an embodiment, the normalized 10g2 activity of a TREM comprising nucleotide substitutions delivered by lentivirus is between about -2 and about 4. In an embodiment, the normalized 10gactivity of a TREM comprising nucleotide substitutions delivered as a synthesized oligonucleotide, e.g., oligo, is between about -2.1 and about 4. 107 WO 2024/216206 PCT/US2024/024492 In an embodiment, a TREM comprises a nucleotide substitution at a nucleotide position relative to a nucleotide position within reference sequence, e.g., a reference TREM. In an embodiment, the TREM comprising the nucleotide substitution modulates, e.g., increases or decreases, a functional parameter of a TREM, e.g., the activity or stability of the TREM, relative to a reference TREM. In an embodiment, the functional parameter of a TREM that is modulated by nucleotide substitution relative to a reference TREM is the premature termination codon (PTC) read-through activity of the TREM. In an embodiment, the PTC read-through activity of a TREM is modulated by a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any ofSEQIDNOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001,2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023. In an embodiment, the PTC read-through activity of a TREM is modulated by a nucleotide substitution relative to SEQ ID NO: 1638. In an embodiment, the PTC read-through activity of a TREM is modulated by a nucleotide substitution relative to SEQ ID NO: 1654. In an embodiment, the PTC read-through activity of a TREM is modulated by a nucleotide substitution relative to SEQ ID NO: 1660. In an embodiment, the PTC read-through activity of a TREM is modulated by a nucleotide substitution relative to SEQ ID NO: 1835. In an embodiment, the PTC read-through activity of a TREM is modulated by a nucleotide substitution relative to SEQ ID NO: 1867. In an embodiment, the PTC read-through activity of a TREM is modulated by a nucleotide substitution relative to SEQ ID NO: 2000. In an embodiment, the PTC read-through activity of a TREM is modulated by a nucleotide substitution relative to SEQ ID NO: 2001. In an embodiment, the PTC read-through activity of a TREM is modulated by a nucleotide substitution relative to SEQ ID NO: 2016. In an embodiment, the PTC read-through activity of a TREM is modulated by a nucleotide substitution relative to SEQ ID NO: 2017. In an embodiment, the PTC read-through activity of a TREM is modulated by a nucleotide substitution relative to SEQ ID NO: 2018. In an embodiment, the PTC read-through activity of a TREM is modulated by a nucleotide substitution relative to SEQ ID NO: 2019. In an embodiment, the PTC read-through activity of a TREM is modulated by a nucleotide substitution relative to SEQ ID NO: 2020. In an embodiment, the PTC read-through activity of a TREM is modulated by a nucleotide substitution relative to SEQ ID NO: 2021. In an embodiment, the PTC read-through activity of a TREM is modulated by a nucleotide substitution relative to SEQ ID NO: 2022. In an embodiment, the PTC read-through activity of a TREM is modulated by a nucleotide substitution relative to SEQ ID NO: 2023. In an embodiment, the PTC read-through activity of a TREM is 108 WO 2024/216206 PCT/US2024/024492 increased by a nucleotide substitution relative to a parent TREM, e.g., a parent TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023. In an embodiment, the PTC read-through activity of a TREM is increased by a nucleotide substitution relative to SEQ ID NO: 1638. In an embodiment, the PTC read-through activity of a TREM is increased by a nucleotide substitution relative to SEQ ID NO; 1654. In an embodiment, the PTC read-through activity of a TREM is increased by a nucleotide substitution relative to SEQ ID NO: 1660. In an embodiment, the PTC read-through activity of a TREM is increased by a nucleotide substitution relative to SEQ ID NO: 1835. In an embodiment, the PTC read-through activity of a TREM is increased by a nucleotide substitution relative to SEQ ID NO: 1867. In an embodiment, the PTC read-through activity of a TREM is increased by a nucleotide substitution relative to SEQ ID NO: 2000. In an embodiment, the PTC read-through activity of a TREM is increased by a nucleotide substitution relative to SEQ ID NO: 2001. In an embodiment, the PTC read-through activity of a TREM is increased by a nucleotide substitution relative to SEQ ID NO: 2016. In an embodiment, the PTC read-through activity of a TREM is increased by a nucleotide substitution relative to SEQ ID NO: 2017. In an embodiment, the PTC read-through activity of a TREM is increased by a nucleotide substitution relative to SEQ ID NO: 2018. In an embodiment, the PTC read-through activity of a TREM is increased by a nucleotide substitution relative to SEQ ID NO: 2019. In an embodiment, the PTC read-through activity of a TREM is increased by a nucleotide substitution relative to SEQ ID NO; 2020. In an embodiment, the PTC read-through activity of a TREM is increased by a nucleotide substitution relative to SEQ ID NO: 2021. In an embodiment, the PTC read-through activity of a TREM is increased by a nucleotide substitution relative to SEQ ID NO: 2022. In an embodiment, the PTC read-through activity of a TREM is increased by a nucleotide substitution relative to SEQ ID NO; 2023.In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001,2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 1% to about 500% or more, e.g., about 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, or more than 500%. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001,2016, 2017, 2018, 2019, 2020, 109 WO 2024/216206 PCT/US2024/024492 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 1%. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001,2016, 2017,2018, 2019,2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 5%. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a parent TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001,2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 10%. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001,2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 20%. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001,2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 30%. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001,2016, 2017,2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 40%. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001,2016, 2017,2018, 2019,2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 50%. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000,2001,2016, 2017,2018, 2019,2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 60%. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000,2001,2016, 2017,2018, 2019,2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 70%. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000,2001,2016, 2017,2018, 2019,2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 80%. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000,2001,2016, 2017,2018, 2019,2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 90%. In an 110 WO 2024/216206 PCT/US2024/024492 embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000,2001,2016, 2017,2018, 2019,2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 100%. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000,2001,2016, 2017,2018, 2019,2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 150%. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000,2001,2016, 2017,2018, 2019,2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 200%. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000,2001,2016, 2017,2018, 2019,2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 250%. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001,2016, 2017,2018, 2019,2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 300%. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001,2016, 2017,2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 350%. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001,2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 400%. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001,2016, 2017,2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 450%. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001,2016, 2017,2018, 2019,2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 500%. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001,2016, 2017,2018, 2019,2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by more than about 500%. ill WO 2024/216206 PCT/US2024/024492 In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 2- fold to about 500-fold or more, e.g., about 2-fold, 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50- fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 250-fold, 300-fold, 350- fold, 400-fold, 450-fold, 500-fold, or more than 500-fold. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 2-fold. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 5-fold. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 10-fold. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 20-fold. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 30-fold. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 40-fold. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 50-fold. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 60-fold. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 112 WO 2024/216206 PCT/US2024/024492 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 70-fold. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 80-fold. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 90-fold. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 100-fold. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 150-fold. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 200-fold. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 250-fold. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 300-fold. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 350-fold. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 400-fold. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, 113 WO 2024/216206 PCT/US2024/024492 increases the PTC read-through of a TREM by about 450-fold. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by about 500-fold. In an embodiment, a nucleotide substitution relative to a reference TREM, e.g., a reference TREM of any of SEQ ID NOs: 1638, 1654, 1660, 1835, 1867, 2000, 2001, 2016, 2017, 2018, 2019, 2020, 2021, 2022, or 2023, increases the PTC read-through of a TREM by more than about 500-fold. In an embodiment, a nucleotide substitution, e.g., a nucleotide substitution listed in FIG. 24, modulates activity of a TREM relative to a reference TREM. In an embodiment, a nucleotide substitution listed in FIG. increases the activity of a TREM relative to a reference TREM. In an embodiment, a nucleotide substitution listed in FIG. 24 decreases the activity of a TREM relative to a reference TREM.In an embodiment, a TREM having a nucleotide substitution is a TREM listed in FIG. 24, e.g., any of SEQ ID NOs: 1457-2001. In an embodiment, the nucleotide substitution is a nucleotide substitution listed in FIG. 24. In an embodiment, the nucleotide substitution increases premature termination codon (PTC) read-through activity of the TREM, e.g., as provided in FIG. 24. In an embodiment, the nucleotide substitution that increases PTC read-through activity of a TREM is a nucleotide substitution comprised by any of SEQ ID NOs: 1469, 1473, 1480, 1639, 1640, 1641, 1642, 1645, 1646, 1649, 1651, 1652, 1654, 1655, 1658, 1659, 1660, 1661, 1662,1665, 1666, 1668, 1669, 1671, 1672, 1673, 1677, 1679, 1680, 1682, 1685, 1686, 1687, 1688,1689, 1694, 1695, 1696, 1697, 1699, 1704, 1705, 1707, 1709, 1711, 1725, 1726, 1727, 1729,1730, 1731, 1732, 1736, 1738, 1739, 1740, 1746, 1750, 1751, 1752, 1758, 1764, 1767, 1768,1769, 1770, 1775, 1777, 1780, 1783, 1792, 1793, 1795, 1797, 1799, 1803, 1808, 1814, 1818,1820, 1823, 1824, 1830, 1832, 1833.In an embodiment, a TREM comprising an Arg-TGA scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1638, comprises a nucleotide substitution at any one of the positions shown in FIG. 6. In an embodiment, a TREM comprising an Arg-TGA scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1638, comprises a nucleotide substitution at any of nucleotide positions 1, 2, 3, 4, 5, 6, or 7, e.g., in the [ASt Domainl], e.g., as shown in FIG. 6. In an embodiment, a TREM comprising an Arg- TGA scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1638, 114 WO 2024/216206 PCT/US2024/024492 comprises a nucleotide substitution at any of nucleotide positions 32, 33, 34, 35, 36, 37, or 38, e.g., in the [ACH Domain], e.g., as shown in FIG. 6. In an embodiment, a TREM comprising an Arg-TGA scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1638, comprises a nucleotide substitution at any of nucleotide positions 65, 66, 67, 68, 69, 70, 71, 72, or 73, e.g., in the [ASt Domain2], e.g., as shown in FIG. 6. In an embodiment, the activity of a TREM comprising an Arg-TGA scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1638, comprising a nucleotide substitution at any of nucleotide positions 1, 2, 3, 4, 5, 6, or 7 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold, about 2-fold, about 3-fold, or about 3.6-fold, e.g., as shown in FIG. 6. In an embodiment, the activity of a TREM comprising an Arg-TGA scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1638, comprising a nucleotide substitution at any of nucleotide positions 32, 33, 34, 35, 36, 37, or 38 is decreased, e.g., relative to a reference sequence, e.g., decreased by about 2-fold, e.g., as shown in FIG. 6. In an embodiment, the activity of a TREM comprising an Arg-TGA scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1638, comprising a nucleotide substitution at any of nucleotide positions 65, 66, 67, 68, 69, 70, 71, 72, or 73 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold, about 2-fold, or about 3.6-fold, e.g., as shown in FIG. 6.In an embodiment, a TREM comprising a Gln-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1835, comprises a nucleotide substitution at any one of the positions shown in FIG. 7. In an embodiment, a TREM comprising a Gln-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1835, comprises a nucleotide substitution at any of nucleotide positions 26, 27, 28, 29, 30, or 31, e.g., in the [ACH Domain], e.g., as shown in FIG. 7. In an embodiment, a TREM comprising a Gln-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1835, comprises a nucleotide substitution at any of nucleotide positions 32, 33, 34, 35, 36, 37, or 38, e.g., in the [ACH Domain], e.g., as shown in FIG. 7. In an embodiment, a TREM comprising a Gln-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1835, comprises a nucleotide substitution at any of nucleotide positions 39, 40, 41, 42, 43, or 44, e.g., in the [ACH Domain], e.g., as shown in FIG. 7. In an embodiment, the activity of a TREM comprising a Gln-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ 115 WO 2024/216206 PCT/US2024/024492 ID NO: 1835, comprising a nucleotide substitution at any of nucleotide positions 26, 27, 28, 29, 30, or 31 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold, about 5-fold, about 6-fold, about 7-fold, or about 8-fold, e.g., as shown in FIG. 7. In an embodiment, the activity of a TREM comprising a Gln-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1835, comprising a nucleotide substitution at any of nucleotide positions 32, 33, 34, 35, 36, 37, or 38 is decreased, e.g., relative to a reference sequence, e.g., decreased by about 2-fold, e.g., as shown in FIG. 7. In an embodiment, the activity of a TREM comprising a Gln-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1835, comprising a nucleotide substitution at any of nucleotide positions 39, 40, 41, 42, 43, or 44 is increased, e.g., relative to a reference sequence, e.g., increased by about 2-fold, about 5-fold, about 6-fold, about 7-fold, or about 8-fold, e.g., as shown in FIG. 7.In an embodiment, a TREM comprising a Gln-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1660 or 1654, comprises a nucleotide substitution at any one of the positions shown in FIG. 8. In an embodiment, a TREM comprising a Gln-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1660 or 1654, comprises a nucleotide substitution at any of nucleotide positions 3, 4, 5, 6, or 7, e.g., in the [ASt Domainl], e.g., as shown in FIG. 8. In an embodiment, a TREM comprising a Gln-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 16or 1654, comprises a nucleotide substitution at nucleotide position 20a, e.g., in the [DH Domain], e.g., as shown in FIG. 8. In an embodiment, a TREM comprising a Gln-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1660 or 1654, comprises a nucleotide substitution at any of nucleotide positions 26, 27, 28, 29, or 30, e.g., in the [ACH Domain], e.g., as shown in FIG. 8. In an embodiment, a TREM comprising a Gln-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1660 or 1654, comprises a nucleotide substitution at any of nucleotide positions 32, 33, 34, 35, 36, 37, or 38, e.g., in the [ACH Domain], e.g., as shown in FIG. 8. In an embodiment, a TREM comprising a Gln-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1660 or 1654, comprises a nucleotide substitution at any of nucleotide positions 40, 41, 42, 43, 44, or 45, e.g., in the [ACH Domain], e.g., as shown in FIG. 8. In an embodiment, a TREM comprising a Gin- TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1660 or 116 WO 2024/216206 PCT/US2024/024492 1654, comprises a nucleotide substitution at nucleotide position 49, e.g., in the [TH Domain], e.g., as shown in FIG. 8. In an embodiment, a TREM comprising a Gln-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1660 or 1654, comprises a nucleotide substitution at any of nucleotide positions 65, 66, 67, 68, 69, 70, 71, 72, or 73, e.g., in the [ASt Domain2], e.g., as shown in FIG. 8. In an embodiment, the activity of a TREM comprising a Gln-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1660 or 1654, comprising a nucleotide substitution at any of nucleotide positions 3, 4, 5, 6, or 7 is increased, e.g., relative to a reference sequence, e.g., increased by about 2.5-fold, about 3-fold, or about 3.5-fold, e.g., as shown in FIG. 8. In an embodiment, the activity of a TREM comprising a Gln-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1660 or 1654, comprising a nucleotide substitution at nucleotide position 20a is increased, e.g., relative to a reference sequence, e.g., increased by about 2.5-fold or about 3-fold, e.g., as shown in FIG. 8. In an embodiment, the activity of a TREM comprising a Gln-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1660 or 1654, comprises a nucleotide substitution at any of nucleotide positions 26, 27, 28, 29, or 30 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold, about 2-fold, or about 2.5-fold, e.g., as shown in FIG. 8. In an embodiment, the activity of a TREM comprising a Gln-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 16or 1654, comprising a nucleotide substitution at any of nucleotide positions 32, 33, 34, 35, 36, 37, or 38 is decreased, e.g., relative to a reference sequence, e.g., decreased by about 2-fold, e.g., as shown in FIG. 8. In an embodiment, the activity of a TREM comprising a Gln-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1660 or 1654, comprising a nucleotide substitution at any of nucleotide positions 40, 41, 42, 43, 44, or 45 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold, about 2-fold, or about 2.5-fold, e.g., as shown in FIG. 8. In an embodiment, the activity of a TREM comprising a Gln-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 16or 1654, comprising a nucleotide substitution at nucleotide position 49 is increased, e.g., relative to a reference sequence, e.g., increased by about 2-fold, e.g., as shown in FIG. 8. In an embodiment, the activity of a TREM comprising a Gln-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1660 or 1654, comprising a nucleotide substitution at any of nucleotide positions 65, 66, 67, 68, 69, 70, 71, 72, or 73 is increased, e.g., 117 WO 2024/216206 PCT/US2024/024492 relative to a reference sequence, e.g., increased by about 1.5-fold, about 2-fold, about 2.5-fold, about 3-fold, or about 3.5-fold, e.g., as shown in FIG. 8.In an embodiment, a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, 2000, or 2001, comprises a nucleotide substitution at any one of the positions shown in FIG 9. In an embodiment, a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, 2000, or 2001, comprises a nucleotide substitution at any of nucleotide positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, e.g., in the [AStDomainl] or the [DH Domain], e.g., as shown in FIG. 9. In an embodiment, a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, 2000, or 2001, comprises a nucleotide substitution at any of nucleotide positions 20a, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31, e.g., in the [DH Domain] or the [ACH Domain], e.g., as shown in FIG. 9. In an embodiment, a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, 2000, or 2001, comprises a nucleotide substitution at any of nucleotide positions 32, 33, 34, 35, 36, 37, or 38, e.g., in the [ACH Domain], e.g., as shown in FIG. 9. In an embodiment, a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, 2000, or 2001, comprises a nucleotide substitution at any of nucleotide positions 40, 41, 42, 43, 44, or 45, e.g., in the [ACH Domain], e.g., as shown in FIG. 9. In an embodiment, a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, 2000, or 2001, comprises a nucleotide substitution at any of nucleotide positions 46 or 48, e.g., in the [VL Domain], e.g., as shown in FIG. 9. In an embodiment, a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, 2000, or 2001, comprises a nucleotide substitution at any of nucleotide positions 59 or 60, e.g., in the [TH Domain], e.g., as shown in FIG. 9. In an embodiment, a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, 2000, or 2001, comprises a nucleotide substitution at any of nucleotide positions 66, 67, 68, 69, 70, 71, 72, or 73, e.g., in the [ASt Domain2], e.g., as shown in FIG. 9. In an embodiment, the activity of a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, 2000, or 2001, comprising a nucleotide substitution at any of nucleotide positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 increases activity, e.g., relative to a 118 WO 2024/216206 PCT/US2024/024492 reference sequence, e.g., increases by about 1.5-fold, about 2-fold, or about 2.5-fold, e.g., as shown in FIG. 9. In an embodiment, the activity of a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO; 1867, 2000, or 2001, comprising a nucleotide substitution at any of nucleotide positions 20a, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5- fold, about 2-fold, about 2.5-fold, or about 3-fold, e.g., as shown in FIG. 9. In an embodiment, the activity of a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO; 1867, 2000, or 2001, comprising a nucleotide substitution at any of nucleotide positions 32, 33, 34, 35, 36, 37, or 38 is decreased, e.g., relative to a reference sequence, e.g., decreased by about 2-fold, e.g., as shown in FIG. 9. In an embodiment, the activity of a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO; 1867, 2000, or 2001, comprising a nucleotide substitution at any of nucleotide positions 40, 41, 42, 43, 44, or 45 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold or about 2-fold, e.g., as shown in FIG. 9. In an embodiment, the activity of a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, 2000, or 2001, comprising a nucleotide substitution at any of nucleotide positions 46 or 48 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold or about 2-fold, e.g., as shown in FIG. 9. In an embodiment, the activity of a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, 2000, or 2001, comprising a nucleotide substitution at any of nucleotide positions 59 or 60 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold, e.g., as shown in FIG. 9. In an embodiment, the activity of a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, 2000, or 2001, comprising a nucleotide substitution at any of nucleotide positions 66, 67, 68, 69, 70, 71, 72, or 73 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold, about 2-fold, or about 2.5-fold, e.g., as shown in FIG. 9.In an embodiment, a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, comprises a nucleotide substitution at any one of the positions shown in FIG. 10. In an embodiment, a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ 119 WO 2024/216206 PCT/US2024/024492 ID NO: 1867, comprises a nucleotide substitution at any of nucleotide positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, e.g., in the [ASt Domainl] or the [DH Domain], e.g., as shown in FIG. 10. In an embodiment, a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, comprises a nucleotide substitution at any of nucleotide positions 20a, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31, e.g., in the [DH Domain] or the [ACH Domain], e.g., as shown in FIG. 10. In an embodiment, a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, comprises a nucleotide substitution at any of nucleotide positions 32, 33, 34, 35, 36, 37, or 38, e.g., in the [ACH Domain], e.g., as shown in FIG. 10. In an embodiment, a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, comprises a nucleotide substitution at any of nucleotide positions 40, 41, 42, 43, 44, or 45, e.g., in the [ACH Domain], e.g., as shown in FIG. 10. In an embodiment, a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, comprises a nucleotide substitution at any of nucleotide positions 46, 48, or 49, e.g., in the [VL Domain], e.g., as shown in FIG. 10. In an embodiment, a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, comprises a nucleotide substitution at any of nucleotide positions 59 or 60, e.g., in the [TH Domain], e.g., as shown in FIG. 10. In an embodiment, a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, comprises a nucleotide substitution at any of nucleotide positions 66, 67, 68, 69, 70, 71, 72, or 73, e.g., in the [ASt Domain2], e.g., as shown in FIG. 10. In an embodiment, the activity of a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, comprising a nucleotide substitution at any of nucleotide positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 increases activity, e.g., relative to a reference sequence, e.g., increases by about 1.5-fold, about 2-fold, about 2.5-fold, or about 3-fold, e.g., as shown in FIG. 10. In an embodiment, the activity of a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, comprising a nucleotide substitution at any of nucleotide positions 20a, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold, about 2-fold, about 2.5-fold, or about 3-fold, e.g., as shown in FIG. 10. In an embodiment, the activity of a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference 120 WO 2024/216206 PCT/US2024/024492 sequence, e.g., SEQ ID NO: 1867, comprising a nucleotide substitution at any of nucleotide positions 32, 33, 34, 35, 36, 37, or 38 is decreased, e.g., relative to a reference sequence, e.g., decreased by about 2-fold, e.g., as shown in FIG. 10. In an embodiment, the activity of a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO; 1867, comprising a nucleotide substitution at any of nucleotide positions 40, 41, 42, 43, 44, or 45 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold or about 2-fold, e.g., as shown in FIG. 10. In an embodiment, the activity of a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO; 1867, comprising a nucleotide substitution at any of nucleotide positions 46 or 48 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold or about 2-fold, e.g., as shown in FIG. 10. In an embodiment, the activity of a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, comprising a nucleotide substitution at any of nucleotide positions 59 or 60 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold, e.g., as shown in FIG. 10. In an embodiment, the activity of a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 1867, comprising a nucleotide substitution at any of nucleotide positions 66, 67, 68, 69, 70, 71, 72, or 73 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold, or about 2-fold, e.g., as shown in FIG. 10.In an embodiment, a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2000, comprises a nucleotide substitution at any one of the positions shown in FIG. 11. In an embodiment, a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2000, comprises a nucleotide substitution at any of nucleotide positions 31 or 32, e.g., in the [ACH Domain], e.g., as shown in FIG. 11. In an embodiment, a TREM comprising a Glu- TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2000, comprises a nucleotide substitution at any of nucleotide positions 32, 33, 34, 35, 36, 37, or 38, e.g., in the [ACH Domain], e.g., as shown in FIG. 11. In an embodiment, the activity of a TREM comprising a Glu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2000, comprising a nucleotide substitution at any of nucleotide positions 31 or 32 is increased, e.g., relative to a reference sequence, e.g., increased by about 5-fold or about 11-fold, e.g., as shown in FIG. 11.In an embodiment, the activity of a TREM comprising a Glu-TAG 121 WO 2024/216206 PCT/US2024/024492 scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2000, comprising a nucleotide substitution at any of nucleotide positions 32, 33, 34, 35, 36, 37, or 38 is decreased, e.g., relative to a reference sequence, e.g., decreased by about 2-fold, e.g., as shown in FIG. 11.In an embodiment, a TREM comprising a Leu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2016 or 2017, comprises a nucleotide substitution at any one of the positions shown in FIG. 12. In an embodiment, a TREM comprising a Leu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2016 or 2017, comprises a nucleotide substitution at any of nucleotide positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30, e.g., in the [ASt Domainl], the [DH Domain], or the [ACH Domain], e.g., as shown in FIG. 12. In an embodiment, a TREM comprising a Leu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2016 or 2017, comprises a nucleotide substitution at any of nucleotide positions 32, 33, 34, 35, 36, 37, or 38, e.g., in the [ACH Domain], e.g., as shown in FIG. 12. In an embodiment, a TREM comprising a Leu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2016 or 2017, comprises a nucleotide substitution at any of nucleotide positions 39, 40, 41, 42, 43, 44, 45, VI1, V12, V13, V14, V15, V16, V17, VI, V2, V3, V4, V5, V27, V26, V25, V24, V23, V22, V21, 46, 47, 48, 49, or 50, e.g., in the [ACH Domain], the [VL Domain], or the [TH Domain], e.g., as shown in FIG. 12. In an embodiment, a TREM comprising a Leu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2016 or 2017, comprises a nucleotide substitution at nucleotide positions 59, e.g., in the [TH Domain], e.g., as shown in FIG. 12. In an embodiment, a TREM comprising a Leu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2016 or 2017, comprises a nucleotide substitution at any of nucleotide positions 64, 65, 66, 67, 68, 69, 70, 71, 72, or 73, e.g., in the [TH Domain] or the [ASt Domain2], e.g., as shown in FIG. 12. In an embodiment, the activity of a TREM comprising a Leu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 20or 2017, comprising a nucleotide substitution at any of nucleotide positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21,22, 23,24, 25,26, 27, 28, 29, or 30 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold or about 2-fold, e.g., as shown in FIG 12. In an embodiment, the activity of a TREM comprising a Leu-TAG scaffold, 122 WO 2024/216206 PCT/US2024/024492 e.g., a TREM corresponding to a reference sequence, e g., SEQ ID NO: 2016 or 2017, comprising a nucleotide substitution at any of nucleotide positions 32, 33, 34, 35, 36, 37, or 38 is decreased, e.g., relative to a reference sequence, e.g., decreased by about 2-fold, e.g., as shown in FIG. 12. In an embodiment, the activity of a TREM comprising a Leu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2016 or 2017, comprising a nucleotide substitution at any of nucleotide positions 39, 40, 41, 42, 43, 44, 45, VI1, V12, V13, V14, V15, V16, V17, VI, V2, V3, V4, V5, V27, V26, V25, V24, V23, V22, V21, 46, 47, 48, 49, or 50 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold or about 2-fold, e.g., as shown in FIG. 12. In an embodiment, the activity of a TREM comprising a Leu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 20or 2017, comprising a nucleotide substitution at nucleotide position 59 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold or about 2-fold, e.g., as shown in FIG. 12. In an embodiment, the activity of a TREM comprising a Leu-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2016 or 2017, comprising a nucleotide substitution at any of nucleotide positions 64, 65, 66, 67, 68, 69, 70, 71, 72, or 73 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold or about 2-fold, e.g., as shown in FIG. 12.In an embodiment, a TREM comprising a Tyr-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2022 or 2023, comprises a nucleotide substitution at any one of the positions shown in FIG. 13. In an embodiment, a TREM comprising a Tyr-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2022 or 2023, comprises a nucleotide substitution at any of nucleotide positions 4, 5, 6, or 7, e.g., in the [ASt Domainl], e.g., as shown in FIG. 13. In an embodiment, a TREM comprising a Tyr-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2022 or 2023, comprises a nucleotide substitution at any of nucleotide positions 16, 17, or 20, e.g., in the [DH Domain], e.g., as shown in FIG. 13. In an embodiment, a TREM comprising a Tyr-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2022 or 2023, comprises a nucleotide substitution at any of nucleotide positions 28, 29, or 30, e.g., in the [ACH Domain], e.g., as shown in FIG. 13. In an embodiment, a TREM comprising a Tyr-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2022 or 2023, comprises a nucleotide substitution at any of nucleotide positions 32, 33, 123 WO 2024/216206 PCT/US2024/024492 34, 35, 36, 37, or 38, e.g., in the [ACH Domain], e.g., as shown in FIG. 13 .In an embodiment, a TREM comprising a Tyr-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2022 or 2023, comprises a nucleotide substitution at any of nucleotide positions 40, 41, 42, 43, or 44, e.g., in the [ACH Domain], e.g., as shown in FIG. 13. In an embodiment, a TREM comprising a Tyr-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2022 or 2023, comprises a nucleotide substitution at any of nucleotide positions 47, 48, 49, 50, or 51, e.g., in the [VL Domain] or the [TH Domain], e.g., as shown in FIG. 13. In an embodiment, a TREM comprising a Tyr-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2022 or 2023, comprises a nucleotide substitution at any of nucleotide positions 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70, e.g., in the [TH Domain] or the [ASt Domain2], e.g., as shown in FIG. 13. In an embodiment, the activity of a TREM comprising a Tyr-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2022 or 2023, comprising a nucleotide substitution at any of nucleotide positions 4, 5, 6, or 7 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold, about 2-fold, or about 2.5-fold, e.g., as shown in FIG. 13. In an embodiment, the activity of a TREM comprising a Tyr-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2022 or 2023, comprising a nucleotide substitution at any of nucleotide positions 16, 17, or 20 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold or about 2-fold, e.g., as shown in FIG. 13. In an embodiment, the activity of a TREM comprising a Tyr-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2022 or 2023, comprising a nucleotide substitution at any of nucleotide positions 28, 29, or 30 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold, about 2-fold, or about 2.5-fold, e.g., as shown in FIG. 13. In an embodiment, the activity of a TREM comprising a Tyr-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2022 or 2023, comprising a nucleotide substitution at any of nucleotide positions 32, 33, 34, 35, 36, 37, or 38 is decreased, e.g., relative to a reference sequence, e.g., decreased by about 2-fold, e.g., as shown in FIG. 13. In an embodiment, the activity of a TREM comprising a Tyr-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2022 or 2023, comprising a nucleotide substitution at any of nucleotide positions 40, 41, 42, 43, or 44 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold, about 2-fold, or about 2.5-fold, e.g., as 124 WO 2024/216206 PCT/US2024/024492 shown in FIG 13. In an embodiment, the activity of a TREM comprising a Tyr-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e g., SEQ ID NO; 2022 or 2023, comprising a nucleotide substitution at any of nucleotide positions 47, 48, 49, 50, or 51 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold, about 2-fold, or about 2.5-fold, e.g., as shown in FIG. 13. In an embodiment, the activity of a TREM comprising a Tyr-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2022 or 2023, comprising a nucleotide substitution at any of nucleotide positions 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold, about 2-fold, or about 2.5-fold, e.g., as shown in FIG. 13.In an embodiment, a TREM comprising a Ser-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2020 or 2021, comprises a nucleotide substitution at any one of the positions shown in FIG. 14. In an embodiment, a TREM comprising a Ser-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2020 or 2021, comprises a nucleotide substitution at any of nucleotide positions 3, 4, 5, or 6, e.g., in the [ASt Domainl], e.g., as shown in FIG. 14. In an embodiment, a TREM comprising a Ser-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2020 or 2021, comprises a nucleotide substitution at any of nucleotide positions 29, 31, 32, or 33, e.g., in the [ACH Domain], e.g., as shown in FIG. 14. In an embodiment, a TREM comprising a Ser-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2020 or 2021, comprises a nucleotide substitution at any of nucleotide positions 34, 35, or 36, e.g., in the [ACH Domain], e.g., as shown in FIG. 14. In an embodiment, a TREM comprising a Ser-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2020 or 2021, comprises a nucleotide substitution at any of nucleotide positions 37, 38, 39, 40, or 41, e.g., in the [ACH Domain], e.g., as shown in FIG. 14. In an embodiment, a TREM comprising a Ser-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2020 or 2021, comprises a nucleotide substitution at nucleotide position 51, e.g., in the [TH Domain], e.g., as shown in FIG. 14. In an embodiment, a TREM comprising a Ser-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2020 or 2021, comprises a nucleotide substitution at nucleotide position 63, e.g., in the [TH Domain], e.g., as shown in FIG. 14. In an embodiment, a TREM comprising a Ser-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2020 or 2021, comprises a nucleotide 125 WO 2024/216206 PCT/US2024/024492 substitution at nucleotide position 67, e.g., in the [ASt Domain2], e.g., as shown in FIG. 14. In an embodiment, the activity of a TREM comprising a Ser-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2020 or 2021, comprising a nucleotide substitution at any of nucleotide positions 3, 4, 5, or 6 is increased, e.g., relative to a reference sequence, e.g., increased by about 2-fold or about 3-fold, e.g., as shown in FIG. 14. In an embodiment, the activity of a TREM comprising a Ser-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2020 or 2021, comprising a nucleotide substitution at any of nucleotide positions 29, 30 31, 32, or 33 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold or about 2-fold, e.g., as shown in FIG. 14. In an embodiment, the activity of a TREM comprising a Ser-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2020 or 2021, comprising a nucleotide substitution at any of nucleotide positions 34, 35, or 36 is decreased, e.g., relative to a reference sequence, e.g., decreased by about 2-fold, e.g., as shown in FIG. 14. In an embodiment, the activity of a TREM comprising a Ser-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2020 or 2021, comprising a nucleotide substitution at any of nucleotide positions 37, 38, 39, 40, or 41 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold, about 2-fold, about 2.5-fold, or about 3-fold, e.g., as shown in FIG. 14. In an embodiment, the activity of a TREM comprising a Ser-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2020 or 2021, comprising a nucleotide substitution at nucleotide position 51 is increased, e.g., relative to a reference sequence, e.g., increased by about 4-fold, e.g., as shown in FIG. 14. In an embodiment, the activity of a TREM comprising a Ser-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2020 or 2021, comprising a nucleotide substitution at nucleotide position 63 is increased, e.g., relative to a reference sequence, e.g., increased by about 4-fold, e.g., as shown in FIG. 14. In an embodiment, the activity of a TREM comprising a Ser-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2020 or 2021, comprising a nucleotide substitution at nucleotide position 67 is increased, e.g., relative to a reference sequence, e.g., increased by about 3-fold, e.g., as shown in FIG. 14.In an embodiment, a TREM comprising a Lys-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2018 or 2019, comprises a nucleotide substitution at any one of the positions shown in FIG. 15. In an embodiment, a TREM 126 WO 2024/216206 PCT/US2024/024492 comprising a Lys-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2018 or 2019, comprises a nucleotide substitution at any of nucleotide positions 1, 2, 3, 4, 5, 6, or 7, e.g., in the [ASt Domain 1], e.g., as shown in FIG. 15. In an embodiment, a TREM comprising a Lys-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO; 2018 or 2019, comprises a nucleotide substitution at any of nucleotide positions 17 or 18, e.g., in the [DH Domain], e.g., as shown in FIG. 15. In an embodiment, a TREM comprising a Lys-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2018 or 2019, comprises a nucleotide substitution at any of nucleotide positions 32, 33, 34, 35, 36, 37, or 38, e.g., in the [ACH Domain], e.g., as shown in FIG. 15. In an embodiment, a TREM comprising a Lys-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO; 2018 or 2019, comprises a nucleotide substitution at nucleotide position 37, e.g., in the [ACH Domain], e.g., as shown in FIG. 15. In an embodiment, a TREM comprising a Lys-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO; 2018 or 2019, comprises a nucleotide substitution at nucleotide position 50, e.g., in the [TH Domain], e.g., as shown in FIG. 15. In an embodiment, a TREM comprising a Lys-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2018 or 2019, comprises a nucleotide substitution at any of nucleotide positions 64, 65, 66, 67, 68, 69, 70, 71, 72, or 73, e.g., in the [DH Domain] or the [ASt Domain2], e.g., as shown in FIG. 15. In an embodiment, the activity of a TREM comprising a Lys-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2018 or 2019, comprising a nucleotide substitution at any of nucleotide positions 1, 2, 3, 4, 5, 6, or 7 is increased, e.g., relative to a reference sequence, e.g., increased by about 1.5-fold, about 2-fold, or about 4-fold, e.g., as shown in FIG. 15. In an embodiment, the activity of a TREM comprising a Lys-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2018 or 2019, comprising a nucleotide substitution at any of nucleotide positions 17 or 18 is increased, e.g., relative to a reference sequence, e.g., increased by about 2-fold or about 3-fold, e.g., as shown in FIG. 15. In an embodiment, the activity of a TREM comprising a Lys-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2018 or 2019, comprising a nucleotide substitution at any of nucleotide positions 32, 33, 34, 35, 36, 37, or 38 is decreased, e.g., relative to a reference sequence, e.g., decreased by about 2-fold, e.g., as shown in FIG. 15. In an embodiment, the activity of a TREM comprising a Lys-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ 127 WO 2024/216206 PCT/US2024/024492 ID NO: 2018 or 2019, comprising a nucleotide substitution at nucleotide position 37 is increased, e.g., relative to a reference sequence, e.g., increased by about 3-fold, e.g., as shown in FIG. 15. In an embodiment, the activity of a TREM comprising a Lys-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2018 or 2019, comprising a nucleotide substitution at nucleotide position 50 is increased, e.g., relative to a reference sequence, e.g., increased by about 3-fold, e.g., as shown in FIG. 15. In an embodiment, the activity of a TREM comprising a Lys-TAG scaffold, e.g., a TREM corresponding to a reference sequence, e.g., SEQ ID NO: 2018 or 2019, comprising a nucleotide substitution at any of nucleotide positions 64, 65, 66, 67, 68, 69, 70, 71, 72, or 73 is increased, e.g., relative to a reference sequence, e.g. increased by about 1.5-fold, about 2-fold, about 2.5-fold, about 3.5-fold, or about 4-fold, e.g., as shown in FIG. 15.

Non-naturally occurring modification A TREM, a TREM core fragment or a TREM fragment described herein may comprise a non-naturally occurring modification, e.g., a modification described in Table 5. A non-naturally occurring modification can be made according to methods known in the art. In an embodiment, a non-naturally occurring modification is a modification that a cell, e.g., a human cell, does not make on an endogenous tRNA. In an embodiment, a non-naturally occurring modification is a modification that a cell, e.g., a human cell, can make on an endogenous tRNA, but wherein such modification is in a location in which it does not occur on a native tRNA. In an embodiment, the non-naturally occurring modification is in a domain, linker or arm which does not have such modification in nature. In an embodiment, the non-naturally occurring modification is at a position within a domain, linker or arm, which does not have such modification in nature. In an embodiment, the non-naturally occurring modification is on a nucleotide which does not have such modification in nature. In an embodiment, the non-naturally occurring modification is on a nucleotide at a position within a domain, linker or arm, which does not have such modification in nature. 128 WO 2024/216206 PCT/US2024/024492 In an embodiment, a TREM, a TREM core fragment or a TREM fragment described herein comprises a modification provided in Table 5, or a combination thereof. The modifications provided in Table 5 are non-naturally occurring or occur naturally in RNAs, and are used herein on a synthetic TREM, a TREM core fragment or a TREM fragment at a position that does not occur in nature. Table 5:Exemplary modifications Chemical Modification (S)-constrained ethyl (cEt) 5 -(m ethoxy carb ony 1 -m ethy l)uraci 1(±) 1 -(2-Hydroxypropyl )pseudouri dine 5-(methyl) 2(thio)uracil(2R)-l-(2-Hydroxypropyl)pseudouridine 5-(methyl) 2,4 (dithio)uracil(2S)-l-(2-Hydroxypropyl)pseudouridine 5-(methyl) 4 (thio)uracil(3 -(3 -amino- 3 -carboxy propyl)uri dine 5-(methyl)-2-(thio)pseudouracil(E)-5-(2-Bromo-vinyl)ara-uridine 5-(methyl)-2-(thio)uracil(E)-5-(2-Bromo-vinyl)cytidine 5-(methyl)-2,4 (dithi o)pseudouracil(E)-5-(2-Bromo-vinyl)uridine 5-(methyl)-2,4-(dithio)uracil(E)-vinylphosphonate 5-(methyl)-4 (thio)pseudouracil(R) 5’-C-methyl 5-(methyl)isocarbostyrilyl(R) 5’-C-methyl with phosphate 5-(methyl)pseudouracil(S) 5’-C-methyl 5-(methylaminomethyl)-2 (thio)uracil(S) 5’-C-methyl with phosphate 5-(methylaminomethyl)-2,4(dithio)uracil(Z)-5-(2-Bromo-vinyl)ara-uridine 5-(methylaminomethyl)-4-(thio)uracil(Z)-5-(2-Bromo-vinyl)uridine 5-(propynyl)uracil(4-Nitro-phenyl)pseudouridine 5-(propynyl)cytosinel-(aminocarbonylethylenyl)-2(thio)- pseudouracil5-(trifluoromethyl)cytosine-(aminocarbonylethylenyl)-2,4- (dithi 0)p seudouracil5-(tri fluorom ethy !)uracil1-(2,2,2-Trifluoroethyl )-pseudouridine 5,2’-O-dimethylcytidinel-(2,2,3,3,3-Pentafluoropropyl)pseudouridine 5,2’-O-dimethyluri dinel-(2,2-Diethoxyethyl)pseudouridine5,6-dihydro-uridinel-(2,4,6-Trimethylbenzyl)pseudouridine 5-Aminoallyl-cytosinel-(2,4,6-Trimethyl-benzyl)pseudo-uridine 5-aminoallyl-uridinel-(2,4,6-Trimethyl-phenyl)pseudo-uridine 5-aminomethy 1 -2-thiouridinel-(2-Amino-2-carboxyethyl)pseudo-uridine 5-aza-2-thio-zebularine-(2-Amino-ethyl)pseudouridine 5-aza-cytidine-(2-Hydroxyethyl)pseudouridine 5-aza-uridine-(2-Methoxyethyl)pseudouridine 5-aza-zebularinel-(3,4-Bis-trifluoromethoxvbenzyl)pseudouridine5-bromo-cytidine 129 WO 2024/216206 PCT/US2024/024492 l-(3,4-Dimethoxybenzyl)pseudouridine 5-bromo-uridinel-(3-Amino-3-carboxypropyl)pseudo-uridine 5-carbamoylmethyl-2 ’-O-methyluridine-(3 - Amino-propyl )pseudouri dine 5-carbamoylmethyluridinel-(3-Cyclopropyl-prop-2-ynyl)pseudouridine TP5-carboxyhydroxymethyluridinel-(4-Amino-4-carboxybutyl )pseudouri dine 5-carboxyhydroxymethyluridine methyl esterl-(4-Amino-benzyl )pseudouri dine 5-carboxymethylaminomethyl-2-thiouridinel-(4-Amino-butyl)pseudouridine5-carboxymethylaminomethyl-2 ’-O- methyluridinel-(4-Amino-phenyl )pseudouridine 5-carboxymethylaminomethyl-2-thiouridine-(4-Azidobenzyl)pseudouridine 5-carboxymethylaminomethyluridinel-(4-Bromobenzyl)pseudouridine 5-carboxymethyluridinel-(4-Chlorobenzyl)pseudouridine 5-Cyanocytidine-(4-Fluorobenzyl)pseudouridine 5-Cyanouridine-(4-Iodobenzyl)pseudouridine 5-Dimethylaminouridinel-(4-Methanesulfonylbenzyl)pseudouridine 5 -Ethy ny 1 ara-cyti di ne-(4-Methoxybenzyl)pseudouridine 5 -Ethy ny 1 cy ti di nel-(4-Methoxy-phenyl)pseudouridine5-formyl-2 ’-O-methylcytidinel-(4-Methylbenzyl)pseudouridine 5-formylcytidinel-(4-Nitrobenzyl)pseudouridine 5 ’ -Homo-adenosinel-(4-Thiomethoxybenzyl)pseudouridine 5’-Homo-cytidinel-(4-Trifluoromethoxybenzyl)pseudouridine 5 ’ -Homo-guanosinel-(4-Trifluoromethylbenzyl)pseudouridine 5’-Homo-uridinel-(5-Amino-pentyl )pseudouri dine 5 -hy droxy m ethy l cy ti di ne-(6-Amino-hexyl)pseudouridine 5-hydroxyuridine1-(aminoalkylamino-carbonylethylenyl)- 2(thio)-pseudouracil5-iodo-2 ’-fluoro-deoxyuridinel-(aminoalkylaminocarbonylethylenyl)-2,4- (dithi 0)p seudouracil5-iodo-cytidine!-(aminoalkyl aminocarbonylethylenyl)- pseudouracil5-iodo-uridinel-(aminoalkylaminocarbonylethylenyl)-4- (thio)pseudouracil5-m ethoxy carbonylmethy 1 -2-thiouridinel-(aminocarbonylethylenyl)-4- (thi o)p seudouraci 15-methoxycarbonylmethyl-2 ’-O- methyluridine1-(aminocarbonylethyleny1)-pseudouracil 5-methoxy carbonylmethyluridinel-(aza)-2-(thio)-3-(aza)-phenoxazin-l-yl 5-Methoxy cytidine1,2’ -O-dimethyl adenosine 5-methoxyuridine1,2’ -O-dimethylguanosine 5-methyl-2-thiouridine1,2’ -O-dimethylinosine 5-methylaminomethyl-2-selenouridine1,3-(diaza)-2-(oxo)-phenthiazin-l -yl 5 -m ethyl am i n om ethyl -2-thi ouri di ne 130 WO 2024/216206 PCT/US2024/024492 1,3-(diaza)-2-(oxo)-phenoxazin- 1 -yl 5-methylaminomethyluridinel,3,5-(triaza)-2,6-(dioxa)-naphthalene 5-methylcytidine1,6-Dimethyl-pseudouridine 5-Methyldihydrouridinel-{3-[2-(2-Aminoethoxy )-ethoxy]- propionvl }pseudouridine5-methyluridine-Acetylpseudouridine 5-methyl-zebularine-Allylpseudouridine 5-nitroindole-Aminomethyl-pseudo-uridine 5-Oxyacetic acid- Uridine1-Benzoylpseudouridine5-Oxyacetic acid-methyl ester-Uridin Nl- methyl-pseudouri dine1-Benzyloxymethylpseudouridine 5-Phenylethynyluridinel-Benzyl-pseudo-uridine 5 ’ -phosphorothioatel-Biotinylpseudouridine 5-propynyl cytosine1-Butyl-pseudo-uridine 5-propynyl uracil-carboxymethyl-pseudouridine 5-taurinomethyl-2-thiouridine-Cyanomethylpseudouridine 5-taurinomethyluridine1-Cyclobutylmethyl-pseudo-uridine5 -Tri deuteromethyl -6-deuterouridine-Cyclobutyl-pseudo-uridine 5 -Tri fluoromethy 1 -Cy ti di ne1-Cycloheptylmethyl-pseudo-uridine 5-Trifluoromethyl-Uridinel-Cycloheptyl-pseudo-uridine 5-uracil1-Cyclohexylmethyl-pseudo-uridine 5-Vinylarauridine-Cyclohexyl-pseudo-uridine 6 (azo)uracil1-Cyclooctylmethyl-pseudo-uridine6-(2,2,2-Trifluoroethyl)-pseudo-uridine1-Cyclooctyl-pseudo-uridine 6-(4-Morpholino)-pseudo-uridine1-Cyclopentylmethyl-pseudo-uridine 6-(4-Thiomorpholino)-pseudo-uridinel-Cyclopentyl-pseudo-uridine 6-(alkyl)guanine1-Cyclopropylmethyl-pseudo-uridine 6-(alkyl)adenine-Cyclopropyl-pseudo-uridine 6-(aza)pyrimidine1-deazaadenosine 6-(azo)cytosinel-Ethyl-pseudo-uridine 6-(azo)thymine1-Hexyl-pseudo-uridine 6-(azo)uracil-Homoallylpseudouridine 6-(methyl)-7-(aza)indolyl1-Hydroxymethylpseudouridine 6-(methyl)adenine1-iso-propyl-pseudo-uridine 6-(methyl)guaninel-Me-2-thio-pseudo-uridine 6-(Substituted-Phenyl)-pseudo-uridinel-Me-4-thio-pseudo-uridine 6-Amino-pseudo-uridine-Me-alpha-thio-pseudo-uridine 6-aza-cytidine1-Me-guanosine 6-aza-uridine1-Methanesulfonylmethylpseudouridine 6-Azido-pseudo-uridine-Methoxymethylpseudouridine 6-Bromo-pseudo-uridine 131 WO 2024/216206 PCT/US2024/024492 1 -Methyl-6-amino-pseudo-uridine 6-Butyl-pseudo-uridine-Methyl-6-bromo-pseudo-uridine 6-Chloro-pseudo-uridine-Methyl-6-cyano-pseudo-uridine 6-chloro-purinel-Methyl-6-hydroxyamino-pseudo-uridine 6-Cyano-pseudo-uridinel-Methyl-6-tri fluoromethoxy-pseudo-uridine 6-Dimethylamino-pseudo-uridine1-methyladenosine 6-Ethoxy-pseudo-uridine-methylguanosine 6-Ethy l carb oxy l ate-p seudo-uri di ne1-methylinosine 6-Ethyl-pseudo-uridine1-methylpseduouridine 6-Fluoro-pseudo-uridine1-methyl-pseudoisocytidine 6-Formyl-pseudo-uridine-methyl-pseudouridine 6-Hydroxyamino-pseudo-uridine-Methyl -p seudo-UTP 6-Hydroxy-pseudo-uridine1-Morpholinomethylpseudouridine 6-Iodo-pseudo-uridine-Pentyl-pseudo-uridine 6-iso-Propyl-pseudo-uridine-Phenyl-pseudo-uridine 6-methoxy-guanosine-Pivaloylpseudouridine 6-Methoxy-pseudo-uridine-Propargylpseudouridine 6-Methylamino-pseudo-uridine-Propyl-pseudo-uridine 6-methyl-guanosine1-propynyl-pseudouridine 6-Methyl-pseudo-uridine1-propynyl-uridine 6-Phenyl-pseudo-uridine-p-tolyl-pseudo-uridine 6-phenyl-pyrrolo-pyrimidin-2-on-3-yl-substituted 2-(thio)-pseudouracil 6-Propyl-pseudo-uridine!-substituted 2,4-(dithio)pseudouracil 6-tert-Butyl-pseudo- uridine-substituted 4-(thio)pseudouracil 6-thio-7-deaza-8-aza-guanosine!-substituted pseudouracil 6-thio-7-deaza-guanosine-taurinomethyl-pseudouridine 6-thio-7-methyl-guanosine1-tert-Butyl-pseudo-uridine 6-thio-guanosine1-Thiomethoxymethylpseudouridine 6-Trifluoromethoxy-pseudo-uridine1-Thiomorpholinomethylpseudouridine 6-Trifluoromethyl-pseudo-uridine1-Tri fluoroacetylpseudouridine 7-(alkyl)guanine1-Tri fluoromethylpseudouridine7-(aminoalkylhydroxy)-l-(aza)-2-(thio)-3- (aza)-phenthiazin- 1 -yl-Vinylpseudouridine7-(aminoalkylhydroxy)-l-(aza)-2-(thio)-3- (aza)-phenoxazin- 1 -yl2-(amino)purine7-(aminoalkylhydroxy)-l,3-(diaza)-2-(oxo)- phenthiazin-l-yl2-(thio)pseudouracil7-(aminoalkylhydroxy)-l,3-(diaza)-2-(oxo)- phenoxazin-l-yl’ -al pha-Ethy ny 1 cy ti dine 7-(aza)indolyl2’-alpha-Ethynylguanosine 7-(deaza)adenine 132 WO 2024/216206 PCT/US2024/024492 2 ’ -al pha-Ethy ny luri dine 7-(deaza)guanine2’-alpha-Tri fluoromethyladenosine7-(guanidiniumalkylhydroxy)-l-(aza)-2- (thio)-3-(aza)-phenoxazinl-yl2’-alpha-Tri fluoromethylguanosine7-(guanidiniumalkylhydroxy)-l-(aza)-2- (thio)-3 -(aza)-phenthiazin- 1 -yl2’-alpha-Tri fluoromethyluridine7-(guanidiniumalkylhydroxy)-l-(aza)-2- (thio)-3 -(aza)-phenoxazin- 1 -yl’ - Amino-2 ‘ -deoxy cytosine7-(guanidiniumalkyl-hydroxy)-l,3-(diaza)-2- (oxo)-phenthiazin-l-yl’ -amino-2 ’ -deoxyribose7-(guanidiniumalkylhydroxy)-l,3-(diaza)-2- (oxo)- phenoxazin- 1 -yl2’-alpha-Tri fluoromethylcytidine 7-(methyl)guanine’ -Azido-2 ’ -deoxy cytosine 7-(propynyl)isocarbostyrilyl’ -azido-2 ’ -deoxyribose 7-(propynyl)isocarbostyrilyl’ - Azido-deoxyuridine 7-propynyl(aza)indolyl2’-beta-Ethynyladenosine 7-aminomethyl-7-deazaguanosine’ -beta-Ethynylguanosine 7-cyano-7-deazaguanosine2’-beta-Ethynyluridine 7-deaza-2- aminopurine2’-beta-Trifluoromethyluridine 7-deaza-2,6-di aminopurine2’-beta-Ethynylcytidine 7-deaza-2-amino-purine’ -brom o-deoxyuri di ne 7-deaza-8-aza-2,6-diaminopurine2’-deoxyuridine 7-deaza-8-aza-2-aminopurine’ -Deoxy-2 ’ ,2 ’ -difluoroadenosine 7-deaza-8-aza-adenine’ -Deoxy-2 ’ ,2 ’ -difluorocytidine 7-deaza-8-aza-adenosine’ -Deoxy-2 ’ ,2 ’ -difluoroguanosine 7-deaza-8-aza-guanosine2’-Deoxy-2 ’,2’-difluorouridine 7-deaza-adenosine2’-Deoxy-2 ’-alpha-aminocytidine 7-deaza-guanosine2’-Deoxy-2 ’-alpha-aminouridine TP 7-deaza-inosinyl’ -Deoxy-2 ’ -alpha-azidocytidine 7-methyl-8-oxo-guanosine2’-Deoxy-2 ’-alpha-azidouridine TP 7-methyladenine’ -Deoxy-2 ’ -alpha-mercaptoadenosine 7-methylguanosine’ -Deoxy-2 ’ -alpha-mercaptocytidine 7-methylinosine’ -Deoxy-2 ’ -alpha-mercaptoguanosine7-substituted l-(aza)-2-(thio)-3-(aza)- phenoxazin-l-yl2’-Deoxy-2 ’-alpha-thiomethoxy adenosine7-substituted l,3-(diaza)-2-(oxo)-phenoxazin- 1-yl2’-Deoxy-2 ’-alpha-thiomethoxy cytidine 8-(alkenyl)adenine2’-Deoxy-2 ’-alpha-thiomethoxy guanosine 8-(alkenyl)guanine’ -Deoxy-2 ’ -alpha-thiomethoxyuridine 8-(alkyl)adenine2’-Deoxy-2 ’-alpha-mercaptouridine 8-(alkyl)guanine2’-Deoxy-2 ’-beta-aminoadenosine 8-(alkynyl )adenine 133 WO 2024/216206 PCT/US2024/024492 2’-Deoxy-2 ’-beta-aminoguanosine 8-(alkynyl)guanine2’-Deoxy-2 ’-beta-aminouridine 8-(amino)adenine’ -Deoxy-2 ’ -beta-azidoadenosine 8-(amino)guanine2’-Deoxy-2 ’-beta-azidocytidine 8-(halo)adenine2’-Deoxy-2 ’-beta-azidoguanosine 8-(halo)guanine’ -Deoxy-2 ’ -beta-azidouri dine 8-(hydroxyl)adenine2’-Deoxy-2 ’-beta-aminocytidine 8-(hydroxyl)guanine2’-Deoxy-2 ’-beta-bromoadenosine 8-(thioalkyl)adenine2’-Deoxy-2 ’-beta-bromocytidine 8-(thioalkyl)guanine2’-Deoxy-2 ’-beta-bromoguanosine 8-(thiol)adenine2’-Deoxy-2 ’-beta-bromouridine 8-(thiol)guanine’ -Deoxy-2 ’ -beta-chloroadenosine 8-Aza-adenosine’ -Deoxy-2 ’ -beta-chlorocy tidine 8-azido-adenosine’ -Deoxy-2 ’ -beta-chloroguanosine 8-bromo-adenosine2’-Deoxy-2 ’-beta-chlorouridine 8-bromo-guanosine’ -Deoxy-2 ’ -beta-fluoroadenosine 8-oxo-guanosine’ -Deoxy-2 ’ -beta-fluorocyti dine 8-Tri fluoromethyladenosine’ -Deoxy-2 ’ -beta-fluoroguanosine 9-(methyl)-imidizopyridinyl’ -Deoxy-2 ’ -beta-fluorouridine 9-Deazaadenosine’ -Deoxy-2 ’ -beta-iodoadenosine 9-Deazaguanosine’ -Deoxy-2 ’ -b eta-i odocy ti di ne alkene containing backbones2’-Deoxy-2 ’-beta-iodoguanosine alkyl phosphonates’ -Deoxy-2 ’ -beta-i odouri dine allyamino-thymidine’ -Deoxy-2 ’ -beta-mercaptoad enosine allyamino-uracil’ -Deoxy-2 ’ -beta-mercaptocytidine alpha-thio-cytidine’ -Deoxy-2 ’ -beta-mercaptoguanosine alpha-thio-guanosine’ -Deoxy-2 ’ -beta-mercaptouridine alpha-thio-pseudo-uridine’ -Deoxy-2 ’ -beta-thiomethoxy adenosine alpha-thio-uridine2’-Deoxy-2 ’-beta-thiomethoxycytidine TP al tri ol’ -Deoxy-2 ’ -b eta-thi omethoxyuri dine aminoalkylphosphoramidates2’-deoxyuridine aminoalkylphosphotriesters’ -F-5 -Methy 1-2 ’ -deoxyuridine aminoindolyl2’-Fluoro anthracenyl2’-fluoro-modif1ed bases archaeosine2’-fluorouridine aza cytosine2’-methyl, 2’-amino, 2’-azido, 2’-fluoro- adenineaza thymidine2’-methyl, 2’-amino, 2’-azido, 2’-fluroo- cytidineaza uracil’ -OH-ara-ad enosine aza adenine 134 WO 2024/216206 PCT/US2024/024492 2 ’ -OH-ara-cytidine azaguanine’ -OH-ara-guanosinebis-ortho-(aminoalkylhydroxy)-6-phenyl- pyrrolo-nvrimidin-2-on-3-yl2’-OH-ara-uridinebis-ortho-substituted-6-phenyl-pyrrolo- pyrimidin-2-on-3 -yl’ -OMe-2- Aminoadenosine boranophosphates’ -OMe- 5 -Me-uri dine -CH2-O-N(CH3)-CH2-’ -OMe-pseudouridine -CH2-N(CH3)-N(CH3)-CH2-’ -O-Methyl -5 -(1 -propyny !)cytidine -CH2-NH-CH2-’ -O-Methyl -5 -(1 -propyny !)uridine chiral phosphonates’ -O-methy !adenosine chiral phosphorothioates2’-O-methylation Constrained nucleic acid (CNA)2’-O-methylcytidine deaza cytosine2’-O-m ethylguanosine deaza guanine2’-O-m ethylinosine deaza thymidine2’-O-methyl-ribose deaza uracil’ -O-methy luri di ne deazaadenine2’-O-ribosyladenosine (phosphate) deoxy-thymidine2-(alkyl)guanine difluorotolyl2-(alkyl)adenine dihydropseudouridine2-(amino)adenine dihydrouridine2-(aminoalkyl)adenine DNA2-(aminopropyl)adenine epoxy queuosine2-(halo)adenine Fluoro hexitol nucleic acid (FHNA)2-(methylthio) N6 (isopentenyl)adenine formacetyl and thioformacetyl backbones2-(propyl)adenine Formycin A2-(propyl)guanine Formycin B2-(thio)cytosine galactosyl-queuosine2-(thio)uracil GNA (glycol nucleic acid)2,2’-anhydro-cytidine hydroxywybutosine2,2’-anhydro-uridine hypoxanthine2,4-(dithio)pseudouracil imidizopyridinyl2,4,5-(trimethyl)phenyl inosinyl2,6-(diamino)purine isocarbostyrilyl2,6-diaminopurine isoguanosine2’-alpha-ethynyladenosine isopentenyladenosine2’-Amino-2 ’-deoxy-guanosine isowyosme2’-Amino-2 ’-deoxy-uridine 1 -Alkyl-6-homoallyl-pseudo-uridine2-amino-6-Chloro-purine-Methyl-6-(2,2,2-Trifluoroethyl)pseudo- uridine 135 WO 2024/216206 PCT/US2024/024492 2-aminoadenine-Methyl-6-(4-thiomorpholino)-pseudo- uridine2-Aminoadenosine 1 -Methyl-6-azido-pseudo-uridine2-aminopurine 1 -Methyl-6-chloro-pseudo-uridine2-Amino-riboside 1 -Methyl -6-di methyl ami no-p seudo-uri dine2-aza-inosinyl 1 -Methyl-6-ethoxy -pseudo-uridine’ -azido-2 ’ -deoxy adenosine 1 -Methyl-6-ethylcarboxylate-pseudo-uridine’ - Azido-2 ’ -deoxy-guanosine 1 -Methyl-6-fluoro-pseudo-uridine2’ -Azido-2 ’ -deoxy-uridine 1 -Methyl-6-hydroxy -pseudo-uridine2-Azidoadenosine 1 -Methyl-6-iodo-pseudo-uridine2’-beta-Trifluoromethyladenosine 1 -Methyl -6-m ethyl amino-p seudo-uri dine2’-beta-Trifluoromethylguanosinel-[3-(2-{2-[2-(2-Aminoethoxy)-ethoxy]- ethoxy }-ethoxy)-propionyl]pseudouri dine2-Bromoadenosine l-Alkyl-6-(l-propynyl)-pseudo-uridine2’-beta-Trifluoromethylcytidine l-Alkyl-6-(2-propynyl)-pseudo-uridine2-Chloroadenosine l-Alkyl-6-allyl-pseudo-uridine2’-Deoxy-2 ’-alpha-aminoadenosine l-Alkyl-6-ethynyl-pseudo-uridine2’-Deoxy-2 ’-alpha-aminoguanosine l-Alkyl-6-vinyl-pseudo-uridine’ -Deoxy-2 ’ -alpha-azidoadenosine 1-Biotinyl-PEG2-pseudouridine2’-Deoxy-2 ’-alpha-azidoguanosine 1-methyl- 1 -deaza-pseudoisocytidine’ -Deoxy-2 ’ -b eta-thi omethoxy guanosine 1-methyl- 1 -deaza-pseudouridine2’-Fluor-N4-Bz-cytidine1-Methyl-3-(3-amino-3- carb oxyproovl )p seudo-Uri dine’ -fluoro-2 ’ -deoxyribosel-Methyl-3-(3-amino-3-carboxypropyl) pseudouridine2-Fluoroadenosinel-methyl-3-(3-amino-5- carb oxy propyl )p seudouri dine’ -Fluoro-N2-i sobutyl -guanosine l-Methyl-6-(4-morpholino)-pseudo-uridine’ -Fluoro-N4-Acetyl -cyti dinel-Methyl-6-(substituted phenyl)pseudo- uridine’ -Fluoro-N6-Bz-deoxy adenosi ne 1 -Methyl -6-buty 1 -p seudo-uri dine2-Iodoadenosine l-Methyl-6-ethyl-pseudo-uridine2-Mercaptoadenosine 1 -Methyl -6-formyl -p seudo-uri dine2-methoxy-4-thio-pseudouridine 1 -Methyl -6-i so-propyl -p seudo-uri dine2-methoxy-4-thio-uridine 1 -Methyl -6-m ethoxy-p seudo-uri dine2-methoxy-5-methyl-cytidine 1-Methyl-6-phenyl-pseudo-uri dine2-methoxy-adenine 1 -Methyl -6-propy 1 -p seud o-uri dine2-methoxy-cytidine l-Methyl-6-tert-butyl-pseudo-uridine2-methoxyuri dine l-methyl-6-thio-guanosine2’-methyl, 2’-amino, 2’-azido, 2’-fluro- guanosinel-Methyl-6-trifluoromethyl-pseudo-uridine 136 WO 2024/216206 PCT/US2024/024492 2’-methyl, 2’-amino, 2’-azido, 2‘fluro-uridine Locked nucleic acid (LNA)2-methyladenosine 1-taurinom ethyl-1-methyl-uridine2-methylpseudouridine l-taurinomethyl-4-thio-uridine2-methylthioadenine lysidine2-methylthio-N6 isopentenyladenosine mannosyl-queuosine2-methylthio-N6-(cis- hydroxyisopentenyl)adenosineMethyl phosphonate2-methylthio-N6-hydroxynorvalyl carbamoyladenosinemethylene (methylimino) 2-methylthio-N6-isopentenyladenosinemethylene formacetyl and thioformacetyl backbones2-methylthio-N6-methyladenosinemethyleneimino and methylenehydrazino backbones2-methylthio-N6-threonyl carbamoyladenosinemethylphosphonates2’-O-methoxyethyl (MOE) methylwyosine2’-O-methoxyethylribose (MOE) morpholino linkages2’-O-m ethyl mosme’ -O-m ethyl adenosine N (methyl)guanine2’-O-methylcytidine -N(CH3)-CH2-CH2-2’-O-m ethylguanosine N-(methyl)guanine’ -O-m ethylinosine N2, 7,2’-O-trimethylguanosine2’O-methyl-N2-isobutyl-guanosine N2,2’-O-dimethy !guanosine2’-O-Methyl-N4-Acetyl-cytidine N2,7-dimethylguanosine2’-0-methyl-N4-Bz-cytidine N2,N2,2’-O-trimethylguanosine2’-O-methyl-N6-Bz-deoxy adenosine N2,N2,7-trimethylgu anosine2’-O-methylpseudouridine N2,N2-dimethyl-6-thio-guanosine’ -O-m ethyluridine N2,N2-dimethylguanosine2’-O-ribosyladenosine (phosphate) N2-isobutyl-guanosine2’-O-ribosy!guanosine (phosphate) N2-methyl-6-thio-guanosine2-oxo-7-aminopyridopyrimidin-3-yl N2-methylguanosine2-oxo-pyridopyrimidine-3-yl N2-substituted purines2-pyridinone N3 (methyl)uracil2-thio-l-methyl-1-deaza-pseudouri dine N4 (acetyl)cytosine2-thi 0-1 -methyl -p seudouri di ne N4,2’-O-dimethylcytidine2-thio-2 ’-O-m ethyluridine N4,N4-Dimethyl-2 ’-OMe-Cytidine2-thio-5-aza-uridine N4-acetyl-2 ’-O-methylcytidine2-thio-5-methyl-cytidine N4-acetylcytidine2-thiocytidine N4-Amino-cytidine2-thio-dihydropseudouri dine N4-B enzoyl -cytidine2-thio-dihydrouri dine N4-methylcytidine 137 WO 2024/216206 PCT/US2024/024492 2-thio-pseudouri dine N6-(19-Amino-pentaoxanonadecyl)adenosine2-thiouridine N6-(ci s-hydroxyi sopentenyl)adenosine2-thio-zebularine N6-(isopentyl)adenine2-Trifluoromethyladenosine N6-(methyl)adenine3-(deaza)-5-(aza)cytosine N6, N6 (dimethyl)adenine3-(methyl)cytosine N6,2’-O-dimethyladenosine3-nitropyrrole N6,N6,2’-O-trimethyladenosine-(3 -amino-3 -carboxypropyl)uracil N6,N6-dimethyladenosine-(3 -amino-3 -carboxypropyl)uridine N6-acetyladenosine3-(alkyl)cytosine N6-ci s-hy droxy-i sopenteny 1-adenosine3-(methyl)-7-(propynyl)isocarbostyrilyl N6-glycinylcarbamoyladenosine3-(methyl)cytidine N6-hydroxynorv alylcarb amoyladenosine3-(methyl)isocarbostyrilyl N6-isopentenyladenosine3,2’-0-dimethyluri dine N6-methyl-2-amino-purine3’-alkylene phosphonates N6-methyladenosine3-alkyl-pseudouridine N6-methyl-N6-threonylcarbamoyladenosine’ -aminophosphorami date N6-substituted purines-deaza-3 -bromoadenosi ne N6-threonylcarbamoyladenosine-deaza-3 -chloroadenosine N-alkylated derivative-deaza-3 -fluoroadenosine napthalenyl3-deaza-3-iodoadenosine nitrobenzimidazolyl3-deazaadenosine nitroimidazolyl’ -ethy ny 1 cy ti dine nitroindazolyl3-methylcytidine nitropyrazolyl3-methyl-pseudouridine N1 -methyl-adenosine3-methyluridine N1 -methyl-guanosine’ -azidoadenosine nubularine4’-azidouridine 06-substituted purines’ -ethynyladenosine O-alkylated derivative4’-ethynylcytidineoligonucleosides with heteroatom internucleoside linkage4’-ethynylguanosineortho-(aminoalkylhydroxy)-6-phenyl-pyrrolo-pyrimidin-2- on-3-yl’ -ethy ny luri dineortho- sub stituted-6-pheny 1 -pyrrol 0-py rimi din- 2-on-3-yl4-(fluoro)-6-(methyl)benzimidazole Oxoformycin TP4-(methyl)benzimidazolepara-(aminoalkylhydroxy)-6-phenyl-pyrrolo- pyrimi din-2-on-3 -yl4-(methyl)indolylpara-substituted-6-phenyl-pyrrolo-pyrimidin- 2-on-3-yl4-(thio)pseudouracil pentacenyl 138 WO 2024/216206 PCT/US2024/024492 4-(thio)uracil peroxywybutosine4,2’-O-dimethyl cytidine phenanthracenyl4,6-(dimethyl)indolyl phenyl4’-azidocytidine phosphinates’ -azidoguanosine phosphonoacetates4’-carbocyclic adenosine phosphoramidates4’-carbocyclic cytidinePhosphorodiamidate Morpholino Oligomer (PMO)4’-carbocyclic guanosine phosphorodithioates4’-carbocyclic uridine Phosphorothioate4-demethylwyosine phosphorothioate internucleoside linkages4-m ethoxy- 1 -methyl-pseudoisocytidinephosphorothioates4-methoxy-2-thio-pseudouridine phosphotriesters4-methoxy-pseudoisocytidine PNA4-methoxy-pseudouridine propynyl-7-(aza)indolyl4-methylcytidine pseudoisocytidine4-thio-l-methyl-l-deaza-pseudoisocytidine Pseudo-iso-cytidine4-thio- 1 -methyl-pseudoisocytidine pseudouracil4-thio- 1 -methyl-pseudouridine pseudouridine4-thio-pseudoi socy ti dinePseudouridine l-(4-methylbenzenesulfonic acid)4-thio-pseudouridine Pseudouridine l-(4-methylbenzoic acid) TP4-thiouracil Pseudouridine 1-methylphosphonic acid4-thiouridine Pseudouridine l-[3-(2-ethoxy)]propionic acid(halo)cytosinePseudouridine l-[3-{2-(2-[2-(2-ethoxy)- ethoxy]-ethoxy)-ethoxy] ]propionic acid (methyl) 4 (thio)uracilPseudouridine 1- [3 - {2-(2- [2- {2(2-ethoxy)- ethoxy } -ethoxy]-ethoxy)-ethoxy } ]propionic acid(methyl)cytosinePseudouridine l-[3-{2-(2-[2-ethoxy]-ethoxy)- ethoxv}]propionic acid(methylaminomethyl)-2 (thio)uracilPseudouridine l-[3-{2-(2-ethoxy)-ethoxv}] propionic acid(methylaminomethyl)-2,4 (dithio)uracilPseudouridine TP 1-methylphosphonic acid diethyl ester(methylaminomethyl)-4 (thio)uracil Pseudo-uridine-1-2-ethanoic acid(propynyl)cytosine Pseudo-uridine-N 1 -5-pentanoic acid(propynyl)uracil Pseudo-uridine-N 1 -3-propionic acid(trifluoromethyl)cytosine Pseudo-uridine-Nl-4-butanoic acid(trifluoromethyl)uracil Pseudo-uridine-N 1-6-hexanoic acidnitroindole Pseudo-uridine-N 1 -methy 1 -p-benzoic acid 139 WO 2024/216206 PCT/US2024/024492 substituted pyrimidines Pseudo-uridine-Nl-p-benzoic acid5-( 1,3 -diazole-l-alkyl)uracil Pseudo-uridine-Nl-7-heptanoic acid-(1 -Propy ny 1 )ara-cy ti di ne pyrenyl5-( 1 -Propynyl)ara-uridine pyridin-4-one ribonucleoside5-(2-aminopropyl)uracil pyridopyrimidin-3-yl5-(2-carbomethoxyvinyl)uridinepyridopyrimidin-3-yl, 2-oxo-7-amino- pyridopyrimidin-3-yl5-(2-Chloro-phenyl)-2-thiocytidine pyrrolo-cytidine5-(2-Furanyl)uridine pyrrolo-pseudoisocytidine5-(4-Amino-phenyl)-2-thiocytidine pyrrolo-pyrimidin-2-on-3-yl-(al ky 1 )-2-(thi o)p seudouracil pyrrol opyrimidinyl5-(alkyl)-4 (thio)pseudouracil pyrrolopyrizinyl5-(alky 1 )-2,4 (dithi0)pseudouracil Pyrrolosine5-(alkyl)cytosine siloxane backbones5-(alkyl)pseudouracil stilbenzyl5-(alkyl)uracil substituted 1,2,4-triazoles5-(alkynyl)cytosine sulfamate backbones5-(alkynyl)uracil sulfide sulfoxide and sulfone backbones5-(allylamino)uracil sulfonate and sulfonamide backbones5-(aminoalkyl)uracil tetracenyl5-(carboxyhydroxymethyl)uridine thio-adenosine5-(carboxyhydroxymethyl)uridine methyl esterthionoalkylphosphonates5-(cyanoalkyl)uracil thionoalkylphosphotriesters-(di al ky 1 ami noalkyl )uraci 1 thionophosphoramidates-(dimethyl ami noalkyl )uracil Tricyclo-DNA (tcDNA)5-(guanidiniumalkyl)uracil tubercidine5-(halo)cytosine undermodified hydroxywybutosine5-(halo)uracil uridine 5-oxyacetic acid5-(i so-Pentenyl ami nomethyl)-2-thiouri dine uridine 5-oxyacetic acid methyl ester5-(i so-Pentenylami nomethyl )-2 ’ -0- methyluridinewybutosine5-(i so-Pentenyl ami nomethyl)uridine wyosme-(1,3 -di azol e- 1 -al ky 1 )uraci 1 xanthine5-(methoxy )uracil Xanthosine5-(methoxycarbonylmethyl)-2-(thio)uracil zebularine A TREM may comprise a non-naturally occurring modification in each of the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the 140 WO 2024/216206 PCT/US2024/024492 [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in each of the [DH Domain] and the [ACH Domain], In some embodiments, the TREM comprises twenty-one non-naturally occurring modifications. In some embodiments, the TREM comprises fifteen 2’-0-methyl modifications. In some embodiments, the TREM comprises one 2’-fluoro modification. In some embodiments, the TREM comprises five phosphorothioate modifications. In some embodiments, the TREM comprises fifteen 2’-O- methyl modifications in the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], one 2’-fluoro modification in the [ACH Domain], and five phosphorothioate modifications in the [DH Domain] and the [ACH Domain], In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No; 1 in Table 6: 1-m, 14-m, 15-m, 16-m, 17-m, 18-m, 19-*, 20-m, 21-*, 33-f, 34-m, 35- *, 37-*, 38-*, 41-m, 42-m, 43-m, 44-m, 50-m, 52-m, 73-m.A TREM may comprise a non-naturally occurring modification in each of the [ASt Domainl] and the [ASt D0main2], In some embodiments, the TREM comprises a nucleotide sugar modification and an internucleotide modification in each of the [ASt Domainl] and the [ASt Domain2], In some embodiments, the TREM comprises six non-naturally occurring modifications. In some embodiments, the TREM comprises three 2’-O-methyl modifications. In some embodiments, the TREM comprises three phosphorothioate modifications. In some embodiments, the TREM comprises three 2’-O-methyl modifications in the [ASt Domainl] and the [ASt Domain2] and three phosphorothioate modifications in the [ASt Domainl] and the [ASt Domain2]. In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 2 in Table 6; 1-m*, 2-m*, 74-*, 75-m.A TREM may comprise a non-naturally occurring modification in each of the [ASt Domainl], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domainl] and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in each of the [ASt Domainl], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises seven non-naturally occurring modifications. In some embodiments, the TREM comprises three 2’-O-methyl modifications. In some embodiments, the TREM comprises four 141 WO 2024/216206 PCT/US2024/024492 phosphorothioate modifications. In some embodiments, the TREM comprises three 2’-O-methyl modifications in the [ASt Domainl] and the [ASt Domain2] and four phosphorothioate modifications in the [ASt Domainl], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No; 3 in Table 6: 1-m*, 2-m*, 52-*, 74-*, 75-m.A TREM may comprise a non-naturally occurring modification in each of the [ASt Domainl], the [DH domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in each of the [DH Domain], the [ACH Domain], and the [TH Domain], In some embodiments, the TREM comprises thirty-one non-naturally occurring modifications. In some embodiments, the TREM comprises twenty-three 2’-O-methyl modifications. In some embodiments, the TREM comprises eight phosphorothioate modifications. In some embodiments, the TREM comprises twenty-three 2’-O-methyl modifications in the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2] and eight phosphorothioate modifications in the [DH Domain], the [ACH Domain], and the [TH Domain], In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 4 in Table 6: 1-m, 2- m, 3-m, 4-m, 5-m, 6-m, 13-m, 14-m, 15-m, 16-m, 17-m, 18-m, 19-*, 20-m, 21-*, 25-m, 33-*, 34- m, 35-*, 37-*, 38-*, 49-m, 50-m, 51-m, 52-m, 53-m, 54-*, 55-*, 61-m, 65-m, 73-m.A TREM may comprise a non-naturally occurring modification in each of the [ASt Domainl], the [DH Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domainl], the [DH Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in each of the [ASt Domainl] and the [ASt Domain2]. In some embodiments, the TREM comprises ten non-naturally occurring modifications. In some embodiments, the TREM comprises four 2’-O-methyl modifications. In some embodiments, the TREM comprises three 2’-fluoro modifications. In some embodiments, the TREM comprises three phosphorothioate modifications. In some embodiments, the TREM comprises four 2’-O- methyl modifications in the [ASt Domainl], the [TH Domain], and the [ASt Domain2], three 2’- 142 WO 2024/216206 PCT/US2024/024492 fluoro modifications in the [DH Domain] and the [TH Domain], and three phosphorothioate modifications in the [ASt Domainl] and the [ASt Domain2]. In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 5 in Table 6: 1-m*, 2- m*, 13-f, 14-f, 54-f, 59-m, 75-*, 76-m.A TREM may comprise a non-naturally occurring modification in each of the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain] and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in each of the [ACH Domain] and the [TH Domain], In some embodiments, the TREM comprises twenty-six non-naturally occurring modifications. In some embodiments, the TREM comprises sixteen 2’-O-methyl modifications. In some embodiments, the TREM comprises two 2’-fluoro modifications. In some embodiments, the TREM comprises eight phosphorothioate modifications. In some embodiments, the TREM comprises sixteen 2’-O- methyl modifications in the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], two 2’-fluoro modifications in the [ACH Domain] and the [VL Domain], and eight phosphorothioate modifications in the [ACH Domain] and the [TH Domain], In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 6 in Table 6: 1-m, 13-m, 17-m, 18-m, 25-m, 33-*, 34-m, 35- *, 37-*, 38-*, 41-f, 42-m, 43-m, 44-f, 49-m, 50-m, 52-m, 54-*, 55-*, 56-m, 57-*, 58-*, 59-m, 61- m, 65-m, 73-m.A TREM may comprise a non-naturally occurring modification in each of the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], In some embodiments, the TREM comprises an internucleotide modification in each of the [DH Domain] and the [TH Domain], In some embodiments, the TREM comprises twenty-five non-naturally occurring modifications. In some embodiments, the TREM comprises nineteen 2’-O-methyl modifications. In some embodiments, the TREM comprises two 2’-fluoro modifications. In some embodiments, the TREM comprises four phosphorothioate modifications. In some embodiments, the TREM comprises nineteen 2’- 143 WO 2024/216206 PCT/US2024/024492 O-methyl modifications in the [ASt Domain 1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], two 2’-fluoro modifications in the [ACH Domain] and the [VL Domain], and four phosphorothioate modifications in the [DH Domain] and the [TH Domain], in some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No; 7 in Table 6: 1-m, 13-m, 14-m, 15-m, 16-m, 17-m, 18-m, 19- *, 20-m, 21-*, 25-m, 41-f, 42-m, 43-m, 44-f, 49-m, 50-m, 51-m, 52-m, 53-m, 54-*, 55-*, 61-m, 65-m, 73-m.A TREM may comprise a non-naturally occurring modification in each of the [ASt Domainl], the [DH Domain], the [ACH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domainl], the [DH Domain], the [ACH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises ten non-naturally occurring modifications. In some embodiments, the TREM comprises eight 2’-O-methyl modifications. In some embodiments, the TREM comprises two 2’-fluoro modifications. In some embodiments, the TREM comprises eight 2’-O-methyl modifications in the [ASt Domainl], the [DH Domain], the [ACH Domain], and the [ASt Domain2] and two 2’-fluoro modifications in the [DH Domain] and the [ACH Domain], In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 8 in Table 6: 1-m, 19-m, 20-m, 21-f, 22-m, 40-f, 41-m, 42-m, 43-m, 73-m.A TREM may comprise a non-naturally occurring modification in each of the [ASt Domainl], the [ACH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domainl], the [ACH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in the [ASt Domainl]. In some embodiments, the TREM comprises sixteen non- naturally occurring modifications. In some embodiments, the TREM comprises thirteen 2’-O- methyl modifications. In some embodiments, the TREM comprises two 2’-fluoro modifications. In some embodiments, the TREM comprises one phosphorothioate modification. In some embodiments, the TREM comprises thirteen 2’-O-methyl modifications in the [ASt Domainl], the [ACH Domain], and the [ASt Domain2], two 2’-fluoro modifications in the [ACH Domain], and one phosphorothioate modification in the [ASt Domainl]. In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 9 in Table 6: 1-m*, 2- m, 3-m, 4-m, 5-m, 6-m, 27-m, 28-m, 29-f, 30-m, 40-f, 41-m, 42-m, 43-m, 73-m. 144 WO 2024/216206 PCT/US2024/024492 A TREM may comprise a non-naturally occurring modification in each of the [ASt Domain 1], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [AStDomainl], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in the [ASt Domainl]. In some embodiments, the TREM comprises twenty-three non-naturally occurring modifications. In some embodiments, the TREM comprises twenty-one 2’-O-methyl modifications. In some embodiments, the TREM comprises one 2’-fluoro modification. In some embodiments, the TREM comprises one phosphorothioate modification. In some embodiments, the TREM comprises twenty-one 2’-O- methyl modifications in the [AStDomainl], the [VL Domain], the [THDomain], and the [ASt Domain2], one 2’-fluoro modification in the [TH Domain], and one phosphorothioate modification in the [ASt Domainl]. In some embodiments, the TREM comprises the non- naturally occurring modification pattern of Pattern No: 10 in Table 6: 1-m*, 2-m, 3-m, 4-m, 5-m, 6-m, 49-m, 50-m, 51-m, 52-m, 53-m, 61-m, 62-m, 63-f, 64-m, 65-m, 66-m, 67-m, 68-m, 69-m, 71-m, 72-m.A TREM may comprise a non-naturally occurring modification in each of the [ASt Domainl], the [DH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domainl], the [DH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in the [ASt Domainl]. In some embodiments, the TREM comprises thirty-one non-naturally occurring modifications. In some embodiments, the TREM comprises twenty-eight 2’-0-methyl modifications. In some embodiments, the TREM comprises one 2’-fluoro modification. In some embodiments, the TREM comprises two phosphorothioate modifications. In some embodiments, the TREM comprises twenty-eight 2’-O-methyl modifications in the [ASt Domainl], the [DH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], one 2’-fluoro modification in the [TH Domain], and two phosphorothioate modifications in the [ASt Domainl]. In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 11 in Table 6: 1-m*, 2-m*, 3-m, 4-m, 5-m, 6-m, 10-m, 11-m, 12-m, 13-m, 22-m, 23-m, 24-m, 25-m, 49-m, 50-m, 51-m, 52-m, 53-m, 54-m, 61-m, 62-m, 63-f, 64-m, 65-m, 66-m, 67-m, 68-m, 73-m. 145 WO 2024/216206 PCT/US2024/024492 A TREM may comprise a non-naturally occurring modification in each of the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], In some embodiments, the TREM comprises an internucleotide modification in each of the [ASt Domainl] and the [ACH Domain], In some embodiments, the TREM comprises thirty-two non-naturally occurring modifications. In some embodiments, the TREM comprises twenty-three 2’-O-methyl modifications. In some embodiments, the TREM comprises four 2’-fluoro modifications. In some embodiments, the TREM comprises five phosphorothioate modifications. In some embodiments, the TREM comprises twenty-three 2’-O-methyl modifications in the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], four 2’-fluoro modifications in the [ACH Domain] and the [VL Domain], and five phosphorothioate modifications in the [ASt Domainl] and the [ACH Domain], In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 12 in Table 6: 1-m*, 2-m*, 3-m, 4-m, 5-m, 6-m, 16-m, 17-m, 18-m, 20-m, 25-m, 33-f, 35-*, 37-*, 38-*, 41-m, 44-m, 45-m, 46-f, 47-f, 48-f, 49-m, 50-m, 51-m, 52-m, 53-m, 54-m, 56-m, 59-m, 73-m.A TREM may comprise a non-naturally occurring modification in each of the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], In some embodiments, the TREM comprises an internucleotide modification in the [ACH Domain], In some embodiments, the TREM comprises twenty-nine non-naturally occurring modifications. In some embodiments, the TREM comprises twenty-one 2’-O-methyl modifications. In some embodiments, the TREM comprises five 2’- fluoro modifications. In some embodiments, the TREM comprises three phosphorothioate modifications. In some embodiments, the TREM comprises twenty-one 2’-O-methyl modifications in the [ASt Domainl], the [DH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], five 2’-fluoro modifications in the [ACH Domain], the [VL Domain], and the [TH Domain], and three phosphorothioate modifications in the [ACH Domain], In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern 146 WO 2024/216206 PCT/US2024/024492 No: 13 in Table 6: 1-m, 2-m, 3-m, 4-m, 5-m, 6-m, 16-m, 17-m, 18-m, 33-f, 35-*, 37-*, 38-*, 44- m, 45-m, 46-f, 47-f, 48-f, 56-m, 59-m, 61-m, 62-m, 63-f, 64-m, 65-m, 66-m, 67-m, 68-m, 73-m.A TREM may comprise a non-naturally occurring modification in each of the [ASt Domainl], the [DH Domain], the [ACH domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domainl], the [DH Domain], the [ACH domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in each of the [ASt Domainl] and the [ACH Domain], In some embodiments, the TREM comprises forty-three non-naturally occurring modifications. In some embodiments, the TREM comprises thirty-one 2’-O-methyl modifications. In some embodiments, the TREM comprises seven 2’-fluoro modifications. In some embodiments, the TREM comprises five phosphorothioate modifications. In some embodiments, the TREM comprises forty-three 2’-O-methyl modifications in the [ASt Domainl], the [DH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], seven 2’-fluoro modifications in the [DH Domain], the [ACH Domain], the [VL Domain], and the [TH Domain], and five phosphorothioate modifications in the [ASt Domainl] and the [ACH Domain], In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 14 in Table 6: 1-m*, 2-m*, 3-m, 4-m, 5-m, 6-m, 10-m, 11-m, 12-m, 13-m, 14-m, 15-f, 16-m, 17-m, 18-m, 19-f, 20-m, 22-m, 23-m, 24-m, 25-m, 33-f, 35-*, 37-*, 38-*, 44-m, 45-m, 46-f, 47-f, 48-f, 56-m, 59-m, 61-m, 62-m, 63-f, 64-m, 65-m, 66-m, 67-m, 68-m, 73-m.A TREM may comprise a non-naturally occurring modification in each of the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in each of the [ASt Domainl] and the [ACH Domain], In some embodiments, the TREM comprises twenty-six non-naturally occurring modifications. In some embodiments, the TREM comprises seventeen 2’-O-methyl modifications. In some embodiments, the TREM comprises four 2’-fluoro modifications. In some embodiments, the TREM comprises five phosphorothioate modifications. In some embodiments, the TREM comprises seventeen 2’-O-methyl modifications in the [ASt Domainl], the [DH Domain], the 147 WO 2024/216206 PCT/US2024/024492 [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], four 2’-fluoro modifications in the [ACH Domain] and the [VL Domain], and five phosphorothioate modifications in the [ASt Domainl] and the [ACH Domain], In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 15 in Table 6: 1-m*, 2-m*, 3-m, 4-m, 5-m, 6-m, 16-m, 17-m, 18-m, 20-m, 25-m, 33-f, 35-*, 37-*, 38-*, 41-m, 44-m, 45-m, 46-f, 47-f, 48-f, 56-m, 59-m, 73-m.A TREM may comprise a non-naturally occurring modification in each of the [ASt Domainl], the [DH Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domainl], the [DH Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises six non-naturally occurring modifications. In some embodiments, the TREM comprises six 2’-O-methyl modifications. In some embodiments, the TREM comprises six 2’-O- methyl modifications in the [ASt Domainl], the [DH Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 16 in Table 6: 1-m, 17-m, 18-m, 50-m, 52-m, 73-m.A TREM may comprise a non-naturally occurring modification in each of the [ASt Domainl], the [DH Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domainl], the [DH Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in the [TH Domain], In some embodiments, the TREM comprises fifteen non-naturally occurring modifications. In some embodiments, the TREM comprises eleven 2’-O-methyl modifications. In some embodiments, the TREM comprises two 2’-fluoro modifications. In some embodiments, the TREM comprises two phosphorothioate modifications. In some embodiments, the TREM comprises eleven 2’-O- methyl modifications in the [ASt Domainl], the [DH Domain], the [TH Domain], and the [ASt Domain2], two 2’-fluoro modifications in the [DH Domain], and two phosphorothioate modifications in the [TH Domain], In some embodiments, the TREM comprises the non- naturally occurring modification pattern of Pattern No: 17 in Table 6: 1-m, 14-m, 15-f, 16-m, 17- m, 18-m, 19-f, 20-m, 54-m*, 55-*, 56-m, 57-m, 59-m, 73-m.A TREM may comprise a non-naturally occurring modification in each of the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the 148 WO 2024/216206 PCT/US2024/024492 [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in each of the [DH Domain], the [ACH Domain], the [VL Domain], and the [TH Domain], In some embodiments, the TREM comprises twenty-nine non-naturally occurring modifications. In some embodiments, the TREM comprises fifteen 2’-O-methyl modifications. In some embodiments, the TREM comprises four 2’-fluoro modifications. In some embodiments, the TREM comprises ten phosphorothioate modifications. In some embodiments, the TREM comprises fifteen 2’-O-methyl modifications in the [ASt Domainl], the [DH Domain], the [ACH Domain], the [TH Domain], and the [ASt Domain2], four 2’-fluoro modifications in the [ACH Domain], the [VL Domain], and the [TH Domain], and ten phosphorothioate modifications in the [DH Domain], the [ACH Domain], the [VL Domain], and the [TH Domain], In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 18 in Table 6: 1-m, 10-m, 13-m, 17-*, 18-m, 19-*, 20-m, 25- m, 29-m, 33-f, 35-*, 37-*, 38-*, 41-f*, 43-m, 44-f, 46-*, 50-m, 52-m, 54-*, 55-*, 56-m, 57-*, 62- m, 63-f, 65-m, 71-m, 73-m.A TREM may comprise a non-naturally occurring modification in each of the [ASt Domainl], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domainl], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises thirteen non-naturally occurring modifications. In some embodiments, the TREM comprises twelve 2’-O-methyl modifications. In some embodiments, the TREM comprises one 2’-fluoro modification. In some embodiments, the TREM comprises twelve 2’-O-methyl modifications in the [ASt Domainl], the [TH Domain], and the [ASt Domain2] and one 2’-fluoro modification in the [ASt Domain2]. In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 19 in Table 6: 1-m, 61-m, 62-m, 64-m, 65-m, 66-m, 67-m, 68-m, 69-m, 70-f, 71-m, 72-m, 73-m.A TREM may comprise a non-naturally occurring modification in each of the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH 149 WO 2024/216206 PCT/US2024/024492 Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in the [ACH Domain], In some embodiments, the TREM comprises nineteen non-naturally occurring modifications. In some embodiments, the TREM comprises thirteen 2’-O-methyl modifications. In some embodiments, the TREM comprises three 2’-fluoro modifications. In some embodiments, the TREM comprises three phosphorothioate modifications. In some embodiments, the TREM comprises thirteen 2’-O-methyl modifications in the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], three 2’-fluoro modifications in the [ACH Domain], and three phosphorothioate modifications in the [ACH Domain], In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 20 in Table 6: 1-m, 14-m, 15-f, 16-m, 17-m, 18-m, 19-f, 20-m, 33-f, 35-*, 37-*, 38-*, 41-m, 42-m, 43-m, 44-m, 50- m, 52-m, 73-m.A TREM may comprise a non-naturally occurring modification in each of the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in the [TH Domain], In some embodiments, the TREM comprises twenty-eight non-naturally occurring modifications. In some embodiments, the TREM comprises twenty-six 2’-O-methyl modifications. In some embodiments, the TREM comprises one 2’- fluoro modification. In some embodiments, the TREM comprises one phosphorothioate modification. In some embodiments, the TREM comprises twenty-six 2’-0-methyl modifications in the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], one 2’-fluoro modification in the [TH Domain], and one phosphorothioate modification in the [TH Domain], In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 21 in Table 6: 1-m, 2-m, 3-m, 4- m, 5-m, 6-m, 14-m, 15-m, 16-m, 17-m, 18-m, 20-m, 25-m, 41-m, 42-m, 43-m, 44-m, 49-m, 50- m, 52-m, 54-m, 55-*, 56-m, 57-f, 59-m, 61-m, 65-m, 73-m.A TREM may comprise a non-naturally occurring modification in each of the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in 150 WO 2024/216206 PCT/US2024/024492 each of the [ASt Domain 1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], In some embodiments, the TREM comprises an internucleotide modification in each of the [ACH Domain] and the [TH Domain], In some embodiments, the TREM comprises thirty-two non-naturally occurring modifications. In some embodiments, the TREM comprises twenty-five 2’-O-methyl modifications. In some embodiments, the TREM comprises three 2’-fluoro modifications. In some embodiments, the TREM comprises four phosphorothioate modifications. In some embodiments, the TREM comprises twenty-five 2’-O-methyl modifications in the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], three 2’-fluoro modifications in the [ACH Domain], the [VL Domain], and the [TH Domain], and four phosphorothioate modifications in the [ACH Domain] and the [TH Domain], In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 22 in Table 6: 1-m, 2-m, 3-m, 4-m, 5-m, 6-m, 14-m, 15-m, 16-m, 17-m, 18-m, 20-m, 25-m, 33-f, 35-*, 37-*, 38-*, 41-m, 42-m, 43-m, 44-f, 49-m, 50-m, 52-m, 54-m, 55-*, 56-m, 57-f, 59- m, 61-m, 65-m, 73-m.A TREM may comprise a non-naturally occurring modification in each of the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in each of the [ACH Domain] and the [TH Domain], In some embodiments, the TREM comprises twenty-seven non-naturally occurring modifications. In some embodiments, the TREM comprises twenty-one 2’-O-methyl modifications. In some embodiments, the TREM comprises one 2’-fluoro modification. In some embodiments, the TREM comprises five phosphorothioate modifications. In some embodiments, the TREM comprises twenty-one 2’-O-methyl modifications in the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], one 2’-fluoro modification in the [ACH Domain], and five phosphorothioate modifications in the [ACH Domain] and the [TH Domain], In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 23 in Table 6: 1-m, 2-m, 3-m, 4-m, 5-m, 6-m, 16- 151 WO 2024/216206 PCT/US2024/024492 m, 17-m, 18-m, 20-m, 25-m, 33-f, 35-*, 37-*, 38-*, 41-m, 42-m, 43-m, 44-m, 49-m, 50-m, 52-m, 54-*, 55-*, 61-m, 65-m, 73-m.A TREM may comprise a non-naturally occurring modification in each of the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in each of the [ACH Domain] and the [TH Domain], In some embodiments, the TREM comprises thirty-four non-naturally occurring modifications. In some embodiments, the TREM comprises twenty-six 2’-O-methyl modifications. In some embodiments, the TREM comprises four 2’-fluoro modifications. In some embodiments, the TREM comprises four phosphorothioate modifications. In some embodiments, the TREM comprises twenty-six 2’-O-methyl modifications in the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], four 2’-fluoro modifications in the [ACH Domain], the [VL Domain], and the [TH Domain], and four phosphorothioate modifications in the [ACH Domain] and the [TH Domain], In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 24 in Table 6: 1-m, 2-m, 3-m, 4-m, 5-m, 6-m, 10-m, 11-m, 12-m, 13-m, 16-m, 17-m, 18-m, 20-m, 25-m, 33-f, 35-*, 37-*, 38-*, 41-f, 42-m, 43-m, 44-f, 49-m, 50-m, 52-m, 54-m, 55-*, 56- m, 57-f, 59-m, 61-m, 65-m, 73-m.A TREM may comprise a non-naturally occurring modification in each of the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in each of the [ACH Domain] and the [TH Domain], In some embodiments, the TREM comprises thirty-seven non-naturally occurring modifications. In some embodiments, the TREM comprises twenty-nine 2’-O-methyl modifications. In some embodiments, the TREM comprises four 2’-fluoro modifications. In some embodiments, the TREM comprises four phosphorothioate modifications. In some embodiments, the TREM comprises twenty-nine 2’-O-methyl modifications in the [ASt Domainl], the [DH Domain], the 152 WO 2024/216206 PCT/US2024/024492 [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], four 2’-fluoro modifications in the [DH Domain], the [ACH Domain], and the [TH Domain], and four phosphorothioate modifications in the [ACH Domain] and the [TH Domain], In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No; 25 in Table 6; 1-m, 2-m, 3-m, 4-m, 5-m, 6-m, 10-m, 11-m, 12-m, 13-m, 14-m, 15-f, 16-m, 17-m, 18-m, 19-f, 20-m, 25-m, 33-f, 35-*, 37-*, 38-*, 41-m, 42-m, 43-m, 44-m, 49-m, 50-m, 52- m, 54-m, 55-*, 56-m, 57-f, 59-m, 61-m, 65-m, 73-m.A TREM may comprise a non-naturally occurring modification in each of the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in each of the [ACH Domain] and the [TH Domain], In some embodiments, the TREM comprises thirty-six non-naturally occurring modifications. In some embodiments, the TREM comprises twenty-eight 2’-O-methyl modifications. In some embodiments, the TREM comprises four 2’-fluoro modifications. In some embodiments, the TREM comprises four phosphorothioate modifications. In some embodiments, the TREM comprises twenty-eight 2’-O-methyl modifications in the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], four 2’-fluoro modifications in the [ACH Domain], the [VL Domain], and the [TH Domain], and four phosphorothioate modifications in the [ACH Domain] and the [TH Domain], In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 26 in Table 6: 1-m, 2-m, 3-m, 4-m, 5-m, 6-m, 16-m, 17-m, 18-m, 20-m, 22-m, 23-m, 24-m, 25-m, 33-f, 35-*, 37-*, 38-*, 41-m, 42-m, 43-m, 44-m, 45-m, 46-f, 48-f, 49-m, 50-m, 52-m, 54- m, 55-*, 56-m, 57-f, 59-m, 61-m, 65-m, 73-m.A TREM may comprise a non-naturally occurring modification in each of the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in the [TH Domain], In some embodiments, the TREM comprises 153 WO 2024/216206 PCT/US2024/024492 thirty-one non-naturally occurring modifications. In some embodiments, the TREM comprises twenty-eight 2’-O-methyl modifications. In some embodiments, the TREM comprises two 2’- fluoro modifications. In some embodiments, the TREM comprises one phosphorothioate modification. In some embodiments, the TREM comprises twenty-eight 2’-O-methyl modifications in the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], two 2’-fluoro modifications in the [TH Domain], and one phosphorothioate modification in the [TH Domain], In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 27 in Table 6: 1-m, 2- m, 3-m, 4-m, 5-m, 6-m, 14-m, 15-m, 16-m, 17-m, 18-m, 20-m, 25-m, 41-m, 42-m, 43-m, 44-m, 49-m, 50-m, 52-m, 54-m, 55-*, 56-m, 57-f, 59-m, 61-m, 62-m, 63-f, 64-m, 65-m, 73-m.A TREM may comprise a non-naturally occurring modification in each of the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in each of the [ACH Domain] and the [TH Domain], In some embodiments, the TREM comprises thirty-three non-naturally occurring modifications. In some embodiments, the TREM comprises twenty-four 2’-O-methyl modifications. In some embodiments, the TREM comprises five 2’-fluoro modifications. In some embodiments, the TREM comprises four phosphorothioate modifications. In some embodiments, the TREM comprises twenty-four 2’-O-methyl modifications in the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], five 2’-fluoro modifications in the [ACH Domain], the [VL Domain], and the [TH Domain], and four phosphorothioate modifications in the [ACH Domain] and the [TH Domain], In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 28 in Table 6: 1-m, 2-m, 3-m, 4-m, 5-m, 6-m, 16-m, 17-m, 18-m, 20-m, 25-m, 33-f, 35-*, 37-*, 38-*, 41-f, 42-m, 43-m, 44-f, 49-m, 50-m, 52-m, 54-m, 55-*, 56-m, 57-f, 59-m, 61-m, 62- m, 63-f, 64-m, 65-m, 73-m.A TREM may comprise a non-naturally occurring modification in each of the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in 154 WO 2024/216206 PCT/US2024/024492 each of the [ASt Domain 1], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain?]. In some embodiments, the TREM comprises an internucleotide modification in each of the [ACH Domain] and the [TH Domain], In some embodiments, the TREM comprises thirty-five non-naturally occurring modifications. In some embodiments, the TREM comprises twenty-six 2’-O-methyl modifications. In some embodiments, the TREM comprises five 2’-fluoro modifications. In some embodiments, the TREM comprises four phosphorothioate modifications. In some embodiments, the TREM comprises twenty-six 2’-O-methyl modifications in the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], five 2’-fluoro modifications in the [ACH Domain], the [VL Domain], and the [TH Domain], and four phosphorothioate modifications in the [ACH Domain] and the [TH Domain], In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 29 in Table 6: 1-m, 2-m, 3-m, 4-m, 5-m, 6-m, 14-m, 15-m, 16-m, 17-m, 18-m, 20-m, 25-m, 33-f, 35-*, 37-*, 38-*, 41-f, 42-m, 43-m, 44-f, 49-m, 50-m, 52-m, 54-m, 55-*, 56-m, 57-f, 59-m, 61-m, 62-m, 63-f, 64-m, 65-m, 73-m.A TREM may comprise a non-naturally occurring modification in each of the [ASt Domainl], the [DH Domain], the [ACH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domainl], the [DH Domain], the [ACH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises sixteen non-naturally occurring modifications. In some embodiments, the TREM comprises fifteen 2’-O-methyl modifications. In some embodiments, the TREM comprises one 2’-fluoro modification. In some embodiments, the TREM comprises fifteen 2’-O-methyl modifications in the [ASt Domainl], the [DH Domain], the [ACH Domain], and the [ASt Domain2] and one 2’-fluoro modification in the [ACH Domain], In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 30 in Table 6: 1-m, 2-m, 3-m, 4-m, 5-m, 6-m, 14-m, 17-m, 18-m, 20-m, 22-m, 25-m, 27-m, 33-f, 71-m, 73-m.A TREM may comprise a non-naturally occurring modification in each of the [ASt Domainl], the [VL Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domainl], the [VL Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification 155 WO 2024/216206 PCT/US2024/024492 in the [ASt Domainl]. In some embodiments, the TREM comprises fourteen non-naturally occurring modifications. In some embodiments, the TREM comprises eleven 2’-0-methyl modifications. In some embodiments, the TREM comprises two 2’-fluoro modifications. In some embodiments, the TREM comprises one phosphorothioate modification. In some embodiments, the TREM comprises eleven 2’-O-methyl modifications in the [ASt Domainl], the [VL Domain], and the [ASt Domain2], two 2’-fluoro modifications in the [VL Domain], and one phosphorothioate modification in the [ASt Domainl]. In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 31 in Table 6: 1-m*, 2-m, 3-m, 4-m, 5-m, 6-m, 44-m, 45-m, 46-f, 47-f, 48-m, 49-m, 73-m.A TREM may comprise a non-naturally occurring modification in each of the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises a nucleotide sugar modification in each of the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2]. In some embodiments, the TREM comprises an internucleotide modification in each of the [ASt Domainl], the [ACH Domain], and the [TH Domain], In some embodiments, the TREM comprises forty-two non-naturally occurring modifications. In some embodiments, the TREM comprises thirty-one 2’-O-methyl modifications. In some embodiments, the TREM comprises four 2’-fluoro modifications. In some embodiments, the TREM comprises seven phosphorothioate modifications. In some embodiments, the TREM comprises thirty-one 2’-O-methyl modifications in the [ASt Domainl], the [DH Domain], the [ACH Domain], the [VL Domain], the [TH Domain], and the [ASt Domain2], four 2’-fluoro modifications in the [ACH Domain], the [VL Domain], and the [TH Domain], and seven phosphorothioate modifications in the [ASt Domainl], the [ACH Domain], and the [TH Domain], In some embodiments, the TREM comprises the non-naturally occurring modification pattern of Pattern No: 32 in Table 6: 1-m*, 2-m*, 3-m, 4-m, 5-m, 6-m, 10-m, 11-m, 12-m, 13-m, 17-m, 18-m, 22-m, 23-m, 24-m, 25-m, 33-f, 35-*, 37-*, 38-*, 41-f, 42-m, 43-m, 44- f, 49-m, 50-m, 51-m, 52-m, 53-m, 54-*, 55-*, 61-m, 62-m, 63-f, 64-m, 65-m, 66-m, 67-m, 68-m, 73-m.

Table 6:Exemplary non-naturally occurring modification patterns of TREMs 156 WO 2024/216206 PCT/US2024/024492 Pattern No. Modification Pattern 1-m, 14-m, 15-m, 16-m, 17-m, 18-m, 19-*, 20-m, 21-*, 33-f, 34-m, 35-*, 37-*, 38-*, 41-m, 42-m, 43-m, 44-m, 50-m, 52-m, 73-m1-m*, 2-m*, 74-*, 75-m1-m*, 2-m*, 52-*, 74-*, 75-m 41-m, 2-m, 3-m, 4-m, 5-m, 6-m, 13-m, 14-m, 15-m, 16-m, 17-m, 18-m, 19-*, 20-m, 21-*, 25-m, 33-*, 34-m, 35-*, 37-*, 38-*, 49-m, 50-m, 51-m, 52-m, 53-m, 54-*, 55- *, 61-m, 65-m, 73-m1-m*, 2-m*, 13-f, 14-f, 54-f, 59-m, 75-*, 76-m1-m, 13-m, 17-m, 18-m, 25-m, 33-*, 34-m, 35-*, 37-*, 38-*, 41-f , 42-m, 43-m, 44- f, 49-m, 50-m, 52-m, 54-*, 55-*, 56-m, 57-*, 58-*, 59-m, 61-m, 65-m, 73-mר1-m, 13-m, 14-m, 15-m, 16-m, 17-m, 18-m, 19-*, 20-m, 21-*, 25-m, 41-f, 42-m, 43- m, 44-f, 49-m, 50-m, 51-m, 52-m, 53-m, 54-*, 55-*, 61-m, 65-m, 73-m1-m, 19-m, 20-m, 21-f, 22-m, 40-f, 41-m, 42-m, 43-m, 73-m1-m*, 2-m, 3-m, 4-m, 5-m, 6-m, 27-m, 28-m, 29-f, 30-m, 40-f, 41-m, 42-m, 43-m, 73-m1-m*, 2-m, 3-m, 4-m, 5-m, 6-m, 49-m, 50-m, 51-m, 52-m, 53-m, 61-m, 62-m, 63-f, 64-m, 65-m, 66-m, 67-m, 68-m, 69-m, 71-m, 72-m 111-m*, 2-m*, 3-m, 4-m, 5-m, 6-m, 10-m, 11-m, 12-m, 13-m, 22-m, 23-m, 24-m, 25-m, 49-m, 50-m, 51-m, 52-m, 53-m, 54-m, 61-m, 62-m, 63-f, 64-m, 65-m, 66-m, 67-m, 68-m,73-m 121-m*, 2-m*, 3-m, 4-m, 5-m, 6-m, 16-m, 17-m, 18-m, 20-m, 25-m, 33-f, 35-*, 37-*, 38-*, 41-m, 44-m, 45-m, 46-f, 47-f, 48-f, 49-m, 50-m, 51-m, 52-m, 53-m, 54-m, 56- m, 59-m, 73-m 131-m, 2-m, 3-m, 4-m, 5-m, 6-m, 16-m, 17-m, 18-m, 33-f, 35-*, 37-*, 38-*, 44-m, 45- m, 46-f, 47-f, 48-f, 56-m, 59-m, 61-m, 62-m, 63-f, 64-m, 65-m, 66-m, 67-m, 68-m, 73-m 141-m*, 2-m*, 3-m, 4-m, 5-m, 6-m, 10-m, 11-m, 12-m, 13-m, 14-m, 15-f, 16-m, 17-m, 18-m, 19-f, 20-m, 22-m, 23-m, 24-m, 25-m, 33-f, 35-*, 37-*, 38-*, 44-m, 45-m, 46-f, 47-f, 48-f, 56-m, 59-m, 61-m, 62-m, 63-f, 64-m, 65-m, 66-m, 67-m, 68-m, 73-m1-m*, 2-m*, 3-m, 4-m, 5-m, 6-m, 16-m, 17-m, 18-m, 20-m, 25-m, 33-f, 35-*, 37-*, 38-*, 41-m, 44-m, 45-m, 46-f, 47-f, 48-f, 56-m, 59-m, 73-m1-m, 17-m, 18-m, 50-m, 52-m, 73-m1-m, 14-m, 15-f, 16-m, 17-m, 18-m, 19-f, 20-m, 54-m*, 55-*, 56-m, 57-m, 59-m, 73- m1-m, 10-m, 13-m, 17-*, 18-m, 19-*, 20-m, 25-m, 29-m, 33-f, 35-*, 37-*, 38-*, 41-f*, 43-m, 44-f, 46-*, 50-m, 52-m, 54-*, 55-*, 56-m, 57-*, 62-m, 63-f, 65-m, 71-m, 73-m1-m, 61-m, 62-m, 64-m, 65-m, 66-m, 67-m, 68-m, 69-m, 70-f, 71-m, 72-m, 73-m1-m, 14-m, 15-f, 16-m, 17-m, 18-m, 19-f, 20-m, 33-f, 35-*, 37-*, 38-*, 41-m, 42-m, 43-m, 44-m, 50-m, 52-m, 73-m 211-m, 2-m, 3-m, 4-m, 5-m, 6-m, 14-m, 15-m, 16-m, 17-m, 18-m, 20-m, 25-m, 41-m, 42-m, 43-m, 44-m, 49-m, 50-m, 52-m, 54-m, 55-*, 56-m, 57-f, 59-m, 61-m, 65-m, 73-m 157 WO 2024/216206 PCT/US2024/024492 221-m, 2-m, 3-m, 4-m, 5-m, 6-m, 14-m, 15-m, 16-m, 17-m, 18-m, 20-m, 25-m, 33-f, 35-*, 37-*, 38-*, 41-m, 42-m, 43-m, 44-f, 49-m, 50-m, 52-m, 54-m, 55-*, 56-m, 57-f, 59-m, 61-m, 65-m, 73-m1-m, 2-m, 3-m, 4-m, 5-m, 6-m, 16-m, 17-m, 18-m, 20-m, 25-m, 33-f, 35-*, 37-*, 38- *, 41-m, 42-m, 43-m, 44-m, 49-m, 50-m, 52-m, 54-*, 55-*, 61-m, 65-m, 73-m 241-m, 2-m, 3-m, 4-m, 5-m, 6-m, 10-m, 11-m, 12-m, 13-m, 16-m, 17-m, 18-m, 20-m, 25-m, 33-f, 35-*, 37-*, 38-*, 41-f, 42-m, 43-m, 44-f, 49-m, 50-m, 52-m, 54-m, 55-*, 56-m, 57-f, 59-m, 61-m, 65-m, 73-m 251-m, 2-m, 3-m, 4-m, 5-m, 6-m, 10-m, 11-m, 12-m, 13-m, 14-m, 15-f, 16-m, 17-m, 18-m, 19-f, 20-m, 25-m, 33-f, 35-*, 37-*, 38-*, 41-m, 42-m, 43-m, 44-m, 49-m, 50- m, 52-m, 54-m, 55-*, 56-m, 57-f, 59-m, 61-m, 65-m, 73-m 261-m, 2-m, 3-m, 4-m, 5-m, 6-m, 16-m, 17-m, 18-m, 20-m, 22-m, 23-m, 24-m, 25-m, 33-f, 35-*, 37-*, 38-*, 41-m, 42-m, 43-m, 44-m, 45-m, 46-f, 48-f, 49-m, 50-m, 52-m, 54-m, 55-*, 56-m, 57-f, 59-m, 61-m, 65-m, 73-m 271-m, 2-m, 3-m, 4-m, 5-m, 6-m, 14-m, 15-m, 16-m, 17-m, 18-m, 20-m, 25-m, 41-m, 42-m, 43-m, 44-m, 49-m, 50-m, 52-m, 54-m, 55-*, 56-m, 57-f, 59-m, 61-m, 62-m, 63-f, 64-m, 65-m, 73-m 281-m, 2-m, 3-m, 4-m, 5-m, 6-m, 16-m, 17-m, 18-m, 20-m, 25-m, 33-f, 35-*, 37-*, 38- *, 41-f, 42-m, 43-m, 44-f, 49-m, 50-m, 52-m, 54-m, 55-*, 56-m, 57-f, 59-m, 61-m, 62-m, 63-f, 64-m, 65-m, 73-m 291-m, 2-m, 3-m, 4-m, 5-m, 6-m, 14-m, 15-m, 16-m, 17-m, 18-m, 20-m, 25-m, 33-f, 35-*, 37-*, 38-*, 41-f, 42-m, 43-m, 44-f, 49-m, 50-m, 52-m, 54-m, 55-*, 56-m, 57-f, 59-m, 61-m, 62-m, 63-f, 64-m, 65-m, 73-m1-m, 2-m, 3-m, 4-m, 5-m, 6-m, 14-m, 17-m, 18-m, 20-m, 22-m, 25-m, 27-m, 33-f, 71-m, 73-m1-m*, 2-m, 3-m, 4-m, 5-m, 6-m, 44-m, 45-m, 46-f, 47-f, 48-m, 49-m, 73-m 321-m*, 2-m*, 3-m, 4-m, 5-m, 6-m, 10-m, 11-m, 12-m, 13-m, 17-m, 18-m, 22-m, 23-m, 24-m, 25-m, 33-f, 35-*, 37-*, 38-*, 41-f, 42-m, 43-m, 44-f, 49-m, 50-m, 51-m, 52-m, 53-m, 54-*, 55-*, 61-m, 62-m, 63-f, 64-m, 65-m, 66-m, 67-m, 68-m, 73-m TREM, TREM core fragment and TREM fragment fusions In an embodiment, a TREM, a TREM core fragment or a TREM fragment disclosed herein comprises an additional moiety, e.g., a fusion moiety. In an embodiment, the fusionmoiety can be used for purification, to alter folding of the TREM, TREM core fragment or TREM fragment, or as a targeting moiety. In an embodiment, the fusion moiety can comprise a tag, a linker, can be cleavable or can include a binding site for an enzyme. In an embodiment, the fusion moiety can be disposed at the N terminal of the TREM or at the C terminal of the TREM, TREM core fragment or TREM fragment. In an embodiment, the fusion moiety can be encodedby the same or different nucleic acid molecule that encodes the TREM, TREM core fragment or TREM fragment. 158 WO 2024/216206 PCT/US2024/024492 TREM Consensus sequence In an embodiment, a TREM disclosed herein comprises a consensus sequence provided herein.In an embodiment, a TREM disclosed herein comprises a consensus sequence of Formula I zzz, wherein zzz indicates any of the twenty amino acids and Formula I corresponds to all species.In an embodiment, a TREM disclosed herein comprises a consensus sequence of Formula II zzz, wherein zzz indicates any of the twenty amino acids and Formula II corresponds to mammals.In an embodiment, a TREM disclosed herein comprises a consensus sequence of Formula III zzz, wherein zzz indicates any of the twenty amino acids and Formula III corresponds to humans.In an embodiment, zzz indicates any of the twenty amino acids: alanine, arginine, asparagine, aspartate, cysteine, glutamine, glutamate, glycine, histidine, isoleucine, methionine, leucine, lysine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine.In an embodiment, a TREM disclosed herein comprises a property selected from the following:a) under physiological conditions residue Ro forms a linker region, e.g., a Linker 1 region;b) under physiological conditions residues R-R2-R3-R4 -R5-R6-R7and residues R65-R66- R67-R68-R69-R70-R71 form a stem region, e.g., an AStD stem region;c) under physiological conditions residues Rg-R9 forms a linker region, e.g., a Linker region;d) under physiological conditions residues -R1o-R 1-R12-R13-R14 R15-R16-R17-R18-R19-R20- R21-R22-R23-R24-R25-R26-R27-R28form a stem-loop region, e.g., a D arm Region;e) under physiological conditions residue -R29 forms a linker region, e.g., a Linker Region;f) under physiological conditions residues -R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40- R41-R42-R43-R44-R45-R46 form a stem-loop region, e.g., an AC arm region;g) under physiological conditions residue -[R47]x comprises a variable region, e.g., as described herein; 159 WO 2024/216206 PCT/US2024/024492 h) under physiological conditions residues -R4s-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58- R59-R6o-R61-R62-R63-R64 form a stem-loop region, e.g., a T arm Region; ori) under physiological conditions residue R72 forms a linker region, e.g., a Linker region.

Alanine TREM Consensus sequenceIn an embodiment, a TREM disclosed herein comprises the sequence of Formula IALA (SEQ ID NO: 562),Ro- R1-R2- Ra-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66־R67- R68-R69-R70-R71-R72, wherein R is a ribonucleotide residue and the consensus for Ala is: Ro= absent; R14, R57=are independently A or absent; R26= A, C, G or absent; R5, R6, Ris, R16, R21, R3o, R31, R32, R34, R37, R41, R42, R43, R44, R45, R48, R49, R50, R58, R59, R63, R64, R66, R67= are independently N or absent; Rn, Rss, R65= are independently A, C, U or absent; R1, R9, R2o, R38, R40, R51, R52, R56= are independently A, G or absent; R7, R22, R25, R27, R29, R46, Rs3, R72= are independently A, G, U or absent; R24, R69= are independently A, U or absent; R70, R71=are independently C or absent; R3, R4= are independently C, G or absent; R12, R33, R36, R62, R68= are independently C, G, U or absent; R13, R17, R2s, R39, Rss, Rso, R61= are independently C, U or absent; R10, R19, R23= are independently G or absent; R2= G, U or absent; R8, R18, R54= are independently U or absent; [R47] x = N or absent; wherein, e.g., x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l- 28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-ll, x=l-10, x=10-271, x=20-271, x=30-271, x=40-271, x=50-271, x=60-271, x=70-271, x=80-271, x=l 00-271, x=l 25-271, x=l 50-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=ll, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, orx=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent. 160 WO 2024/216206 PCT/US2024/024492 In an embodiment, a TREM disclosed herein comprises the sequence of Formula Hala (SEQ ID NO: 563),Ro- R1-R2- R-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x־R48־R49־R50־R51־R52־R53־R54־R55־R56־R57־R58־R59־R60־R61־R62־R63־R64־R65־R66־R67־ R6s-R69-R70-R71-R72wherein Risa ribonucleotide residue and the consensus for Ala is:Ro, R!8= are absent;R14, R24, R57=are independently A or absent;R15, R26, R64= are independently A, C, G or absent;R16, R31, R50, R59= are independently N or absent;Rn, R32, R37, R41, R43, R45, R49, R65, R66= are independently A, C, U or absent;R1, R5, R9, R25, R27, R38, R40, R46, R51, R56= are independently A, G or absent;R7, R22, R29, R42, R44, R53, R63, R72= are independently A, G, U or absent;R6, R35, R69= are independently A, U or absent;R55, R60, R70, R71= are independently C or absent;R3= C, G or absent;R12, R36, R48= are independently C, G, U or absent;R13, R17, R28, R30, R34, R39, R58, R61, R62, R67, R68= are independently C, U or absent;R4, Rio, R19, R20, R23, R52= are independently G or absent;R2, R8, R33= are independently G, U or absent;R21, R54= are independently U or absent; [R47] x = N or absent;wherein, e.g., x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-l l, x=l-10, x=10-271, x=20-271, x=30-271, x=40-271, x=50-271, x=60-271, x-70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=ll, x=12, x=13, x=14, x=15, x=16, x=17, 161 WO 2024/216206 PCT/US2024/024492 x=1 8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.In an embodiment, a TREM disclosed herein comprises the sequence of Formula IIIALA (SEQ ID NO: 564),Ro- R1-R2- R-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66-R67- R68-R69-R70-R71 -Rwherein Risa ribonucleotide residue and the consensus for Ala is:Ro, R!8= are absent; R14, R24, R57, R72=are independently A or absent;R15, R26, R64= are independently A, C, G or absent; Ris, R31, R5o= are independently N or absent;Rn, R32, R37, R41, R43, R45, R49, R65, R6s= are independently A, C, U or absent;R5, R9, R25, R27, R38, R40, R46, R51, R56= are independently A, G or absent; R7, R22, R29, R42, R44, R53, R63= are independently A, G, U or absent;R6, R35= are independently A, U or absent;R55, Rso, Rs1, R70, R71= are independently C or absent; R12, R48, R59= are independently C, G, U or absent;R13, R17, R28, R30, R34, R39, R58, R62, R67, R68= are independently C, U or absent; R1, R2, R3, R4, Rio, R19, R20, R23, R52= are independently G or absent;R33, R3s= are independently G, U or absent;R8, R21, R54, R69= are independently U or absent; [R47] x = N or absent;wherein, e.g., x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-l l, x=l-10, x=10-271, x=20-271, x=30-271, x=40-271, x=50-271, x=60-271, x=70- 162 WO 2024/216206 PCT/US2024/024492 271, x=80-271, x=l 00-271, x=l 25-271, x=l 50-271, x=l 75-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=ll, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.Arginine TREM Consensus sequenceIn an embodiment, a TREM disclosed herein comprises the sequence of Formula I arg (SEQ ID NO: 565),Ro- R1-R2- R3-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66־R67- R68-R69-R70-R71-R72wherein Risa ribonucleotide residue and the consensus for Arg is:R57=A or absent; R9,R27=are independently A,C,G or absent;R1,R2,R3,R4,R5,R6,R7,R11,R12,R16,R21,R22,R23,R25,R26,R29,R3O,R31,R32,R33,R34,R37,R42,R44,R45, R46,R48,R49,R50,R51,R58,R62,R63,R64,R65,R66,R67,R68,R69,R70,R71=are independently N or absent; R13,R17,R41=are independently A,C,U or absent;R19,R20,R24,R40,R56=are independently A,G or absent;R14,R15,R72=are independently A,G,U or absent; R18= A,U or absent;R38= C or absent; R35,R43,R61=are independently C,G,U or absent;R28,R55,R59,R60=are independently C,U or absent;R0,R10,R52=are independently G or absent; R8,R39=are independently G,U or absent;R36,R53,R54=are independently U or absent;[R47] x = N or absent; 163 WO 2024/216206 PCT/US2024/024492 wherein, e.g., x=l-271 (e.g., x=1-250, x=l-225, x=l-200, x=1-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-ll, x=l-10, x= 10-271, x=20-271, x=3 0-271, x=40-271, x=50-271, x=60-271, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=l l, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.In an embodiment, a TREM disclosed herein comprises the sequence of Formula II arg (SEQ ID NO: 566),Ro- R1-R2- R-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66־R67- R68-R69-R70-R71-R72wherein Risa ribonucleotide residue and the consensus for Arg is:R18= absent;R24,R57=are independently A or absent; R41= A,C or absent;R3,R7,R34,R50=are independently A,C,G or absent;R2,R5,R6,R12,R26,R32,R37,R44,R58,R66,R67,R68,R70=are independently N or absent; R49,R71=are independently A,C,U or absent;R1,R15,R19,R25,R27,R40,R45,R46,R56,R72=are independently A,G or absent;R14,R29,R63=are independently A,G,U or absent;R16,R21=are independently A,U or absent;R38,R61=are independently C or absent;R33,R48=are independently C,G or absent;R4,R9,R11,R43,R62,R64,R69=are independently C,G,U or absent; R13,R22,R28,R30,R3!,R35,R55,R60,R65=are independently C,U or absent; 164 WO 2024/216206 PCT/US2024/024492 R0,R10,R20,R23,R51,R52=are independently G or absent;R8,R39,R42=are independently G,U or absent;R17,R36,R53,R54,R59=are independently U or absent; [R47] x = N or absent;wherein, e.g., x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l18 ־, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-l l, x=l-10, x=10-271, x=20-271, x=30-271, x=40-271, x=50-271, x=60-271, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=ll, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.In an embodiment, a TREM disclosed herein comprises the sequence of Formula III arg (SEQ ID NO: 567),Ro- R1-R2- R-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66־R67- R68-R69-R70-R71-R72wherein Risa ribonucleotide residue and the consensus for Arg is:R18=is absent;R15,R21,R24,R41,R57=are independently A or absent;R34,R44=are independently A,C or absent;R3,R5,R58=are independently A,C,G or absent; R2,R6,R66,R70=are independently N or absent;R37,R49=are independently A,C,U or absent;R1,R25,R29,R40,R45,R46,R50=are independently A,G or absent;R14,R63,R68=are independently A,G,U or absent;R16= A,U or absent; 165 WO 2024/216206 PCT/US2024/024492 R38,R61=are independently C or absent;R7,R11,R12,R26,R48=are independently C,G or absent;R64,R67,R69=are independently C,G,U or absent;R4,R13,R22,R28,R30,R31,R35,R43,R55,R60,R62,R65,R71=are independently C,U or absent; Ro,R1o,R19,R2o,R23,R27,R33,R51,R52,R56,R72=are independently G or absent;R8,R9,R32,R39,R42=are independently G,U or absent;R17,R36,R53,R54,R59=are independently U or absent; [R47] x = N or absent;wherein, e.g, x=l-271 (e.g, x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x= 1 -12, x= 1 -11, x= 1 -10, x= 10-271, x=20-27 1, x=3 0-271, x=40-27 1, x=50-27 1, x=60-27 1, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=ll, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.Asparagine TREM Consensus sequenceIn an embodiment, a TREM disclosed herein comprises the sequence of Formula 1 asn (SEQ ID NO: 568),Ro- R1-R2- R-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63־R64-R65-R66-R67- R68-R69-R70-R71-Rwherein Risa ribonucleotide residue and the consensus for Asn is:Ro,R18=are absent;R4!= A or absent;R14,R48,R56=are independently A,C,G or absent; R2,R4,R5,R6,R12,R17,R26,R29,R3O,R31,R44,R45,R46,R49,R5O,R58,R62,R63,R65,R66,R67,R68,R7O,R71~ are independently N or absent; 166 WO 2024/216206 PCT/US2024/024492 Ru,R13,R22,R42,R55,R59=are independently A,C,U or absent; R9,R15,R24,R27,R34,R37,R51,R72=are independently A,G or absent; R1,R7,R25,R69=are independently A,G,U or absent;R40,R57=are independently A,U or absent;R6o= C or absent;R33= C,G or absent;R21,R32,R43,R64=are independently C,G,U or absent;R3,R16,R28,R35,R36,R61=are independently C,U or absent; R10,R19,R20,R52=are independently G or absent;R54= G,U or absent;R8,R23,R38,R39,R53=are independently U or absent; [R47] x = N or absent;wherein, e.g., x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-l l, x=l-10, x=10-271, x=20-271, x=30-271, x=40-271, x=50-271, x=60-271, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=l l, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.In an embodiment, a TREM disclosed herein comprises the sequence of Formula II asn (SEQ ID NO: 569),Ro- R1-R2- Ra-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66־R67- R68-R69-R70-R71-Rwherein Risa ribonucleotide residue and the consensus for Asn is:Ro,R18=are absent 167 WO 2024/216206 PCT/US2024/024492 R24,R41,R46,R62=are independently A or absent; R59= A,C or absent;R14,R56,R66=are independently A,C,G or absent;R17,R29=are independently N or absent;R11,R26,R42,R55=are independently A,C,U or absent;R1,R9,R12,R15,R25,R34,R37,R48,R51,R67,R68,R69,R70,R72=are independently A,G or absent;R44,R45,R58=are independently A,G,U or absent;R40,R57=are independently A,U or absent;R5,R28,R60=are independently C or absent;R33,R65=are independently C,G or absent;R2!,R43,R7!=are independently C,G,U or absent;R3,R6,R13,R22,R32,R35,R36,R61,R63,R64=are independently C,U or absent;R7,R!0,R19,R20,R27,R49,R52=are independently G or absent; R54= G,U or absent;R2,R4,R8,R16,R23,R30,R31,R38,R39,R50,R53=are independently U or absent; [R47] x = N or absent;wherein, e.g, x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-l 1, x=l-10, x= 10-271, x=20-271, x=3 0-271, x=40-271, x=50-271, x=60-271, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=ll, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.In an embodiment, a TREM disclosed herein comprises the sequence of Formula III asn (SEQ ID NO: 570),Ro- R1-R2- R-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- 168 WO 2024/216206 PCT/US2024/024492 R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66־R67- R68-R69-R70-R71-R72wherein Risa ribonucleotide residue and the consensus for Asn is:Ro,R18=are absentR24,R40,R4!,R46,R62=are independently A or absent; R59= A,C or absent;R14,R56,R66=are independently A,C,G or absent;R11,R26,R42,R55=are independently A,C,U or absent;R1,R9,R12,R15,R34,R37,R48,R51,R67,R68,R69,R70=are independently A,G or absent; R44,R45,R58=are independently A,G,U or absent; R57= A,U or absent;R5,R28,R60=are independently C or absent;R33,R65=are independently C,G or absent;R17,R21,R29=are independently C,G,U or absent;R3,R6,R13,R22,R32,R35,R36,R43,R6!,R63,R64,R71=are independently C,U or absent;R7,R10,R19,R20,R25,R27,R49,R52,R72=are independently G or absent; R54= G,U or absent;R2,R4,R8,R16,R23,R30,R31,R38,R39,R50,R53=are independently U or absent; [R47] x = N or absent;wherein, e.g., x=l-271 (e.g., x=1-250, x=l-225, x=l-200, x=1-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-ll, x=l-10, x= 10-271, x=20-271, x=3 0-271, x=40-271, x=50-271, x=60-271, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=l l, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent. 169 WO 2024/216206 PCT/US2024/024492 Aspartate TREM Consensus sequenceIn an embodiment, a TREM disclosed herein comprises the sequence of Formula I asp (SEQ ID NO: 571),Ro- R1-R2- Ra-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x־R48־R49־R50־R51־R52־R53־R54-R55־R56־R57־R58־R59־R60־R61־R62־R63־R64־R65־R66־R67־ R68-R69-R70-R71-R72wherein Risa ribonucleotide residue and the consensus for Asp is:Ro=absentR24,R71=are independently A,C or absent;R33,R46=are independently A,C,G or absent; R2,R3,R4,R5,R6,R12,R16,R22,R26,R29,R31,R32,R44,R48,R49,R58,R63,R64,R66,R67,R68,R69=are independently N or absent;R13,R21,R34,R4!,R57,R65=are independently A,C,U or absent; R9,R10,R14,R15,R20,R27,R37,R40,R51,R56,R72=are independently A,G or absent;R7,R25,R42=are independently A,G,U or absent;R39= C or absent; R50,R62=are independently C,G or absent;R30,R43,R45,R55,R70=are independently C,G,U or absent;R8,Ru,R17,R18,R28,R35,R53,R59,R60,R61=are independently C,U or absent; R19,R52=are independently G or absent;R1= G,U or absent; R23,R36,R38,R54=are independently U or absent;[R47] x = N or absent;wherein, e.g, x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x= 1 -12, x= 1 -11, x= 1 -10, x= 10-271, x=20-27 1, x=3 0-271, x=40-27 1, x=50-27 1, x=60-27 1, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=ll, x=12, x=13, x=14, x=15, x=16, x=17, 170 WO 2024/216206 PCT/US2024/024492 x=1 8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.In an embodiment, a TREM disclosed herein comprises the sequence of Formula II asp (SEQ ID NO: 572),Ro- R1-R2- R-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48־R49־R50-R51־R52-R53־R54-R55־R56־R57-R58־R59-R60־R61־R62־R63־R64-R65־R66-R67־ R68-R69-R70-R71 -R72wherein Risa ribonucleotide residue and the consensus for Asp is:R0R17R18R23=are independently absent;R9,R40=are independently A or absent; R24,R71=are independently A,C or absent;R67,R68=are independently A,C,G or absent; R2,R6,R،arc independently N or absent;R57,R63=are independently A,C,U or absent; R10,R14,R27,R33,R37,R44,R46,R51,R56,R64,R72=are independently A,G or absent;R7,R12,R26,R65=are independently A,U or absent; R39,R61,R62=are independently C or absent;R3,R31,R45,R70=are independently C,G or absent;R4,R5,R29,R43,R55=are independently C,G,U or absent; R8,R11,R13,R30,R32,R34,R35,R41,R48,R53,R59,R60=are independently C,U or absent; R15,R19,R20,R25,R42,R50,R52=are independently G or absent;R1,R22,R49,R58,R69=are independently G,U or absent;R16,R21,R28,R36,R38,R54=are independently U or absent; [R47] x = N or absent;wherein, e.g., x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, 171 WO 2024/216206 PCT/US2024/024492 x=1-12, x=l-ll, x=l-10, x=l 0-271, x=20-271, x=30-271, x=40-271, x=50-271, x=60-271, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=l l, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.In an embodiment, a TREM disclosed herein comprises the sequence of Formula III asp (SEQ ID NO: 573),Ro- R1-R2- R-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48־R49־R50־R51־R52-R53־R54-R55־R56־R57־R58־R59-R60־R61־R62־R63־R64־R65־R66-R67־ R68-R69-R70-R71 -R72wherein Risa ribonucleotide residue and the consensus for Asp is:R0,R17,R18,R23=are absent R9,R12,R40,R65,R71=are independently A or absent;R2,R24,R57=are independently A,C or absent;R6,R14,R27,R46,R51,R56,R64,R67,R68=are independently A,G or absent; R3,R31,R35,R39,R61,R62=are independently C or absent; R66= C,G or absent;R5,R8,R29,R30,R32,R34,R41,R43,R48,R55,R59,R60,R63=are independently C,U or absent; R10,R15,R19,R20,R25,R33,R37,R42,R44,R45,R49,R50,R52,R69,R70,R72—are independently G or absent;R22,R58=are independently G,U or absent;R1,R4,R7,Ru,R13,R16,R21,R26,R28,R36,R38,R53,R54=are independently U or absent; [R47] x = N or absent;wherein, e.g., x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-l l, x=l-10, x=10-271, x=20-271, x=30-271, x=40-271, x=50-271, x=60-271, x=70- 172 WO 2024/216206 PCT/US2024/024492 271, x=80-271, x=l 00-271, x=l 25-271, x=l 50-271, x=l 75-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=ll, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.Cysteine TREM Consensus sequenceIn an embodiment, a TREM disclosed herein comprises the sequence of Formula 1 cys (SEQ ID NO: 574),Ro- R1- R2- R3-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66־R67- R68-R69-R70-R71-R72wherein R is a ribonucleotide residue and the consensus for Cys is:Ro =absent R14,R39,R57=are independently A or absent;R41= A,C or absent;R10,R15,R27,R33,R62=are independently A,C,G or absent;R3,R4,R5,R6,R12,R13,R16,R24,R26,R29,R3O,R31,R32,R34,R42,R44,R45,R46,R48,R49,R58,R63,R64,R66, R67,R68,R69,R70=are independently N or absent;R65= A,C,U or absent;R9,R25,R37,R40,R52,R56=are independently A,G or absent;R7,R20,R51=are independently A,G,U or absent;R18,R38,R55=are independently C or absent; R2= C, G or absent;R21,R28,R43,R50=are independently C,G,U or absent;Ru,R22,R23,R35,R36,R59,R60,R61,R71,R72=are independently C,U or absent;R1,R19=are independently G or absent;R17= G,U or absent; R8,R53,R54=are independently U or absent; 173 WO 2024/216206 PCT/US2024/024492 [R47] x = N or absent;wherein, e.g., x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-l l, x=l-10, x=10-271, x=20-271, x=30-271, x=40-271, x=50-271, x=60-271, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=ll, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.In an embodiment, a TREM disclosed herein comprises the sequence of Formula II cys (SEQ ID NO: 575),Ro- R1- R2- R3-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66־R67- R68-R69-R70-R71-R72wherein R is a ribonucleotide residue and the consensus for Cys is:Ro,R18,R23=are absent;R14,R24,R26,R29,R39,R41,R45,R57=are independently A or absent; R44= A,C or absent;R27,R62=are independently A,C,G or absent; R16= A,C,G,U or absent;R30,R70=are independently A,C,U or absent;R5,R7,R9,R25,R34,R37,R40,R46,R52,R56,R58,R66=are independently A,G or absent; R20,R51=are independently A,G,U or absent;R35,R38,R43,R55,R69=are independently C or absent;R2,R4,R15=are independently C,G or absent; R13= C,G,U or absent;R6,R11,R28,R36,R48,R49,R50,R60,R61,R67,R68,R71,R72=are independently C,U or absent; 174 WO 2024/216206 PCT/US2024/024492 R1,R3,R10,R19,R33,R63=are independently G or absent;R8,R17,R21,R64=are independently G,U or absent;R12,R22,R31,R32,R42,R53,R54,R65=are independently U or absent; R59= U, or absent; [R47] x = N or absent;wherein, e.g, x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x= 1 -12, x= 1 -11, x= 1 -10, x= 10-271, x=20-27 1, x=3 0-271, x=40-27 1, x=50-27 1, x=60-27 1, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=l l, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.In an embodiment, a TREM disclosed herein comprises the sequence of Formula III cys (SEQ ID NO: 576),Ro- Ri- R2- R-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63־R64-R65-R66-R67- R68-R69-R70-R71-R72wherein R is a ribonucleotide residue and the consensus for Cys is:R0R18R23=are absentR14,R24,R26,R29,R34,R39,R41,R45,R57,R58=are independently A or absent;R44,R70=are independently A,C or absent; R62= A,C,G or absent;R16= N or absent;R5,R7,R9,R20,R40,R46,R51,R52,R56,R66=are independently A,G or absent;R28,R35,R38,R43,R55,R67,R69=are independently C or absent;R4,R15=are independently C,G or absent; 175 WO 2024/216206 PCT/US2024/024492 R6,R11,R13,R30,R48,R49,R50,R60,R61,R68,R71,R72=are independently C,U or absent;R1,R2,R3,R10,R19,R25,R27,R33,R37,R63=are independently G or absent;R8,R21,R64=are independently G,U or absent;R12,R17,R22,R31,R32,R36,R42,R53,R54, R59,R65=are independently U or absent; [R47] x = N or absent;wherein, e.g., x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-l l, x=l-10, x=10-271, x=20-271, x=30-271, x=40-271, x=50-271, x=60-271, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=l l, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.Glutamine TREM Consensus sequenceIn an embodiment, a TREM disclosed herein comprises the sequence of Formula 1 gln (SEQ ID NO: 577),Ro- Ri- R2- R3-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66־R67- R68-R69-R70-R71-R72wherein R is a ribonucleotide residue and the consensus for Gin is:Ro,R18=are absent;R14,R24,R57=are independently A or absent; R9,R26,R27,R33,R56=are independently A,C,G or absent;R2,R4,R5,R6,R12,R13,R16,R21,R22,R25,R29,R30,R31,R32,R34,R41,R42,R44,R45,R46,R48,R49,R50,R58,R 62,R63,R66,R67,R68,R69,R70=are independently N or absent;R17,R23,R43,R65,R71=are independently A,C,U or absent;R15,R40,R51,R52=are independently A,G or absent;R1,R7,R72=are independently A,G,U or absent; 176 WO 2024/216206 PCT/US2024/024492 R3,R1 l,R37,Reo,R64=are independently C,G,U or absent;R28,R35,R55,R59,R61=are independently C,U or absent;R10,R!9,R20=are independently G or absent; R39= G,U or absent;R8,R36,R38,R53,R54=are independently U or absent; [R47] x = N or absent;wherein, e.g., x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-ll, x=l-10, x=10-271, x=20-271, x=30-271, x=40-271, x=50-271, x=60-271, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=ll, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.In an embodiment, a TREM disclosed herein comprises the sequence of Formula II gln (SEQ ID NO: 578),Ro- R1-R2- R3-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66־R67- R6s-R69-R70-R71-R72wherein R is a ribonucleotide residue and the consensus for Gin is:Ro,R18R23=are absentR14,R24,R57=are independently A or absent; R17,R71=are independently A,C or absent;R25,R26,R33,R44,R46,R56,R69=are independently A,C,G or absent; R4,R5,R12,R22,R29,R30,R48,R49,R63,R67,R68=are independently N or absent; R31,R43,R62,R65,R70=are independently A,C,U or absent;R15,R27,R34,R40,R41,R51,R52=are independently A,G or absent; 177 WO 2024/216206 PCT/US2024/024492 R2,R7,R21,R45,R50,R58,R66,R72=are independently A,G,U or absent;R3,R13,R32,R37,R42,R60,R64=are independently C,G,U or absent; R6,R!L,R28,R35,R55,R59,R61=are independently C,U or absent;R9,R10,R19,R20=are independently G or absent;R1,R16,R39=are independently G,U or absent;R8,R36,R38,R53,R54=are independently U or absent; [R47] x = N or absent;wherein, e.g., x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-l l, x=l-10, x=10-271, x=20-271, x=30-271, x=40-271, x=50-271, x=60-271, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=l l, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.In an embodiment, a TREM disclosed herein comprises the sequence of Formula III gln (SEQ ID NO: 579),Ro- R1-R2- R3-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66־R67- R68-R69-R70-R71-R72wherein R is a ribonucleotide residue and the consensus for Gin is:Ro,R18,R23=are absent R14,R24,R41,R57=are independently A or absent;R17,R7!=are independently A,C or absent;R5,R25,R26,R46,R56,R69=are independently A,C,G or absent;R4,R22,R29,R30,R48,R49,R63,R68=are independently N or absent;R43,R62,R65,R70=are independently A,C,U or absent; 178 WO 2024/216206 PCT/US2024/024492 R15,R27,R33,R34,R40,R51,R52=are independently A,G or absent;R2,R7,R12,R45,R50,R58,R66=are independently A,G,U or absent; R31= A,U or absent;R32,R44,R60=are independently C,G or absent;R3,R13,R37,R42,R64,R67=are independently C,G,U or absent;R6,R1L,R28,R35,R55,R59,R61=are independently C,U or absent;R9,R10,R19,R20=are independently G or absent;R1,R21,R39,R72=are independently G,U or absent;R8,R16,R36,R38,R53,R54=are independently U or absent; [R47] x = N or absent;wherein, e.g., x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x= 1 -12, x= 1 -11, x= 1 -10, x= 10-271, x=20-27 1, x=3 0-271, x=40-27 1, x=50-27 1, x=60-27 1, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=l l, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.Glutamate TREM Consensus sequence In an embodiment, a TREM disclosed herein comprises the sequence of Formula 1 glu (SEQ ID NO: 580),Ro- Ri- R2- R3-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66־R67- R68-R69-R70-R71-Rwherein R is a ribonucleotide residue and the consensus for Glu is:Ro=absent; 179 WO 2024/216206 PCT/US2024/024492 R34,R43,R68,R69=are independently A,C,G or absent; Rl,R2,R5,R6,R9,R12,R16,R20,R21,R26,R27,R29,R30,R31,R32,R33,R41,R44,R45,R46,R48,R50,R51,R58,R3,R64,R65,R66,R70,R7!=are independently N or absent;R13,R17,R23,R61=are independently A,C,U or absent;R10,R14,R24,R40,R52,R56=are independently A,G or absent;R7,R15,R25,R67,R72=are independently A,G,U or absent; Ru,R57=are independently A,U or absent; R39= C,G or absent;R3,R4,R22,R42,R49,R55,R62=are independently C,G,U or absent; R18,R28,R35,R37,R53,R59,R60=are independently C,U or absent;R19= G or absent; R8,R36,R38,R54=are independently U or absent; [R47] x = N or absent;wherein, e.g., x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x= 1 -12, x= 1 -11, x= 1 -10, x= 10-271, x=20-27 1, x=3 0-271, x=40-27 1, x=50-27 1, x=60-27 1, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=l l, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.In an embodiment, a TREM disclosed herein comprises the sequence of Formula II glu (SEQIDNO: 581),Ro- Ri- R2- R3-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63־R64-R65-R66-R67- R68-R69-R70-R71-Rwherein R is a ribonucleotide residue and the consensus for Glu is: 180 WO 2024/216206 PCT/US2024/024492 Ro,R18R23=are absentR17,R40=are independently A or absent;R26,R27,R34,R43,R68,R69,R71=are independently A,C,G or absent;R1,R2,R5,R12,R21,R31,R33,R41,R45,R48,R51,R58,R66,R70=are independently N or absent; R44,R61=are independently A,C,U or absent;R9,R14,R24,R25,R52,R56,R63=are independently A,G or absent;R7,R15,R46,R50,R67,R72=are independently A,G,U or absent;R29,R57=are independently A,U or absent; R6o= C or absent;R39= C,G or absent;R3,R6,R20,R30,R32,R42,R55,R62,R65=are independently C,G,U or absent;R4,R8,R16,R28,R35,R37,R49,R53,R59=are independently C,U or absent;R10,R19=are independently G or absent;R22,R64=are independently G,U or absent;R11,R13,R36,R38,R54=are independently U or absent; [R47] x = N or absent;wherein, e.g, x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-l 1, x=l-10, x= 10-271, x=20-271, x=3 0-271, x=40-271, x=50-271, x=60-271, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=ll, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.In an embodiment, a TREM disclosed herein comprises the sequence of Formula III glu (SEQ ID NO: 582),Ro- R1-R2- R-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- 181 WO 2024/216206 PCT/US2024/024492 R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66־R67- R68-R69-R70-R71-R72wherein R is a ribonucleotide residue and the consensus for Glu is:Ro,R17R18,R23=are absentR14,R27,R40,R7!=are independently A or absent;R44= A,C or absent;R43= A,C,G or absent;R1,R31,R33,R45,R51,R66=are independently N or absent;R21,R41=are independently A,C,U or absent;R7,R24,R25,R50,R52,R56,R63,R68,R70=are independently A,G or absent;R5,R46=are independently A,G,U or absent;R29,R57,R67,R72=are independently A,U or absent;R2,R39,R60=are independently C or absent;R3,R12,R20,R26,R34,R69=are independently C,G or absent;R6,R3o,R42,R48,R65=are independently C,G,U o rabsent;R4,R16,R28,R35,R37,R49,R53,R55,R58,R61,R62=are independently C,U or absent;R9,R10,R!9,R64=are independently G or absent;R15,R22,R32=are independently G,U or absent;R8,R11,R13,R36,R38,R54,R59=are independently U or absent;[R47] x = N or absent;wherein, e.g, x=l-271 (e.g, x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-l 1, x=l-10, x= 10-271, x=20-271, x=3 0-271, x=40-271, x=50-271, x=60-271, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=ll, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), 182 WO 2024/216206 PCT/US2024/024492 provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.Glycine TREM Consensus sequenceIn an embodiment, a TREM disclosed herein comprises the sequence of Formula 1 gly (SEQ ID NO: 583),Ro- R1-R2- R3-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48־R49־R50־R51־R52־R53־R54-R55־R56־R57־R58־R59־R60־R61־R62־R63־R64־R65־R66־R67־ R68-R69-R70-R71-R72wherein R is a ribonucleotide residue and the consensus for Gly is:Ro=absent; R24= A or absent;R3,R9,R40,R50,R51=are independently A,C,G or absent; R4,R5,R6,R7,R12,R16,R21,R22,R26,R29,R30,R31,R32,R33,R34,R41,R42,R43,R44,R45,R46,R48,R49,R58,R 63,R64,R65,R66,R67,R68=are independently N or absent;R59= A,C,U or absent;R1,R10,R14,R15,R27,R56=are independently A,G or absent;R20,R25=are independently A,G,U or absent;R57,R72=are independently A,U or absent;R38,R39,R60=are independently C or absent;R52= C,G or absent;R2,R19,R37,R54,R55,R61,R62,R69,R70=are independently C,G,U or absent; R11,R13,R17,R28,R35,R36,R71=are independently C,U or absent;R8,R!8,R23,R53=are independently U or absent; [R47] x = N or absent;wherein, e.g., x=l-271 (e.g, x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-l l, x=l-10, x=10-271, x=20-271, x=30-271, x=40-271, x=50-271, x=60-271, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, 183 WO 2024/216206 PCT/US2024/024492 x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=l l, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.In an embodiment, a TREM disclosed herein comprises the sequence of Formula II gly (SEQ ID NO: 584),Ro- Ri- R2- R3-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66־R67- R68-R69-R70-R71-R72wherein R is a ribonucleotide residue and the consensus for Gly is:Ro,R18,R23=are absentR24,R27,R40,R72=are independently A or absent;R26= A,C or absent;R3,R7,R68=are independently A,C,G or absent;R5,R30,R41,R42,R44,R49,R67=are independently A,C,G,U or absent;R31,R32,R34=are independently A,C,U or absent;R9,R10,R14,R!5,R33,R50,R56=are independently A,G or absent;R12,R16,R22,R25,R29,R46=are independently A,G,U or absent; R57= A,U or absent;R17,R38,R39,R60,R61,R71=are independently C or absent;R6,R52,R64,R66=are independently C,G or absent;R2,R4,R37,R48,R55,R65=are independently C,G,U or absent;R13,R35,R43,R62,R69=are independently C,U or absent;R1,R!9,R20,R51,R70=are independently G or absent;R21,R45,R63=are independently G,U or absent;R8,R11,R28,R36,R53,R54,R58,R59=are independently U or absent; [R47] x = N or absent; 184 WO 2024/216206 PCT/US2024/024492 wherein, e.g., x=l-271 (e.g., x=1-250, x=l-225, x=l-200, x=1-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-ll, x=l-10, x= 10-271, x=20-271, x=3 0-271, x=40-271, x=50-271, x=60-271, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=l l, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.In an embodiment, a TREM disclosed herein comprises the sequence of Formula III gly (SEQ ID NO: 585),Ro- R1-R2- Ra-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66־R67- R68-R69-R70-R71-R72wherein R is a ribonucleotide residue and the consensus for Gly is:Ro,R18,R23=are absentR24,R27,R40,R72=are independently A or absent; R26= A,C or absent;R3,R7,R49,R68=are independently A,C,G or absent;R5,R30,R41,R44,R67=are independently N or absent;R31,R32,R34=are independently A,C,U or absent;R9,R10,R14,R15,R33,R50,R56=are independently A,G or absent;R12,R25,R29,R42,R46=are independently A,G,U or absent;R16,R57=are independently A,U or absent;R17,R38,R39,R60,R61,R71=are independently C or absent;R6,R52,R64,R66=are independently C,G or absent;R37,R48,R65=are independently C,G,U or absent;R2,R4,R13,R35,R43,R55,R62,R69=are independently C,U or absent; 185 WO 2024/216206 PCT/US2024/024492 R1,R19,R20,R51,R70=are independently G or absent;R21,R22,R45,R63=are independently G,U or absent; R8,R1L,R28,R36,R53,R54,R58,R59=are independently U or absent; [R47] x = N or absent;wherein, e.g., x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-l l, x=l-10, x=10-271, x=20-271, x=30-271, x=40-271, x=50-271, x=60-271, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=ll, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.Histidine TREM Consensus sequenceIn an embodiment, a TREM disclosed herein comprises the sequence of Formula 1 his (SEQ ID NO: 586), Ro- R1-R2- Ra-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66־R67- R68-R69-R70-R71-Rwherein Risa ribonucleotide residue and the consensus for His is:R23=absent;R14,R24,R57=are independently A or absent; R72= A,C or absent;R9,R27,R43,R48,R69=are independently A,C,G or absent; R3,R4,R5,R6,R12,R25,R26,R29,R3O,R31,R34,R42,R45,R46,R49,R5O,R58,R62,R63,R66,R67,R68=are independently N or absent;R13,R21,R41,R44,R65=are independently A,C,U or absent;R40,R51,R56,R70=are independently A,G or absent;R7,R32=are independently A,G,U or absent; 186 WO 2024/216206 PCT/US2024/024492 R55,R60=are independently C or absent; R11,R16,R33,R64=are independently C,G,U or absent;R2,R17,R22,R28,R35,R53,R59,R61,R71=are independently C,U or absent; R1,R10,R15,R19,R20,R37,R39,R52=are independently G or absent; Ro= G,U or absent;R8,R18,R36,R38,R54=are independently U or absent; [R47] x = N or absent;wherein, e.g., x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-l l, x=l-10, x=10-271, x=20-271, x=30-271, x=40-271, x=50-271, x=60-271, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=l l, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.In an embodiment, a TREM disclosed herein comprises the sequence of Formula II his (SEQ ID NO: 587),Ro- R1-R2- R3-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66־R67- R68-R69-R70-R71-Rwherein Risa ribonucleotide residue and the consensus for His is:Ro,R17R18,R23=are absent; R7,R12,R14,R24,R27,R45,R57,R58,R63,R67,R72=are independently A or absent; R3= A,C,U or absent;R4,R43,R56,R70=are independently A,G or absent; R49= A,U or absent;R2,R28,R30,R4!,R42,R44,R48,R55,R60,R66,R71=are independently C or absent; 187 WO 2024/216206 PCT/US2024/024492 R25= C,G or absent;R9= C,G,U or absent;R8,R13,R26,R33,R35,R50,R53,R6!,R68=are independently C,U or absent;R1,R6,R10,R15,R19,R20,R32,R34,R37,R39,R40,R46,R51,R52,R62,R64,R69=are independently G or absent; R16= G,U or absent;R5,R11,R21,R22,R29,R31,R36,R38,R54,R59,R65=are independently U or absent; [R47] x = N or absent;wherein, e.g, x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x= 1 -12, x= 1 -11, x= 1 -10, x= 10-271, x=20-27 1, x=3 0-271, x=40-27 1, x=50-27 1, x=60-27 1, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=ll, x=12, x=13, x=14, x=15, x=16, x=17, x=l 8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x-70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x-200, x-225, x-250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.In an embodiment, a TREM disclosed herein comprises the sequence of Formula III his (SEQ ID NO: 588),Ro- R1-R2- R-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60־R61-R62-R63-R64-R65-R66-R67- R68-R69-R70-R7I-Rwherein Risa ribonucleotide residue and the consensus for His is:Ro.R17R18R23=are absentR7,R12,R14,R24,R27,R45,R57,R58,R63,R67,R72=are independently A or absent;R3= A,C or absent; R4,R43,R56,R70=are independently A,G or absent; R49= A,U or absent; 188 WO 2024/216206 PCT/US2024/024492 R2,R28,R30,R4!,R42,R44,R48,R55,R60,R66,R71=are independently C or absent;R8,R9,R26,R33,R35,R50,R61,R68=are independently C,U or absent;R1,R6,R!0,R15,R19,R20,R25,R32,R34,R37,R39,R40,R46,R51,R52,R62,R64,R69=are independently G or absent;R5,Rn,R13,R16,R21,R22,R29,R31,R36,R38,R53,R54,R59,R65=are independently U or absent; [R47] x = N or absent;wherein, e.g., x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-l 1, x=l-10, x= 10-271, x=20-271, x=3 0-271, x=40-271, x=50-271, x=60-271, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=ll, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.Isoleucine TREM Consensus sequence In an embodiment, a TREM disclosed herein comprises the sequence of Formula I ile(SEQ ID NO: 589),Ro- Ri- R2- R3-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66־R67- R68-R69-R70-R71-R72wherein R is a ribonucleotide residue and the consensus for He is:R23=absent;R38,R41,R57,R72=are independently A or absent;R1,R26=are independently A,C,G or absent; R0,R3,R4,R6,R16,R31,R32,R34,R37,R42,R43,R44,R45,R46,R48,R49,R5O,R58,R59,R62,R63,R64,R66,R67,R 68,R69=are independently N or absent; R22,R61,R65=are independently A,C,U or absent;R9,R14,R!5,R24,R27,R40=are independently A,G or absent; 189 WO 2024/216206 PCT/US2024/024492 R7,R25,R29,R51,R56=are independently A,G,U or absent;R18,R54=are independently A,U or absent; R6o= C or absent;R2,R52,R70=are independently C,G or absent;R5,R12,R21,R30,R33,R71=are independently C,G,U or absent; Ru,R13,R17,R28,R35,R53,R55=are independently C,U or absent;R10,R19,R20=are independently G or absent;R8,R36,R39=are independently U or absent; [R47] x = N or absent;wherein, e.g., x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-ll, x=l-10, x=10-271, x=20-271, x=30-271, x=40-271, x=50-271, x=60-271, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=ll, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.In an embodiment, a TREM disclosed herein comprises the sequence of Formula II ile (SEQ ID NO: 590),Ro- R1- R2- R3-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66־R67- R68-R69-R70-R71-R72wherein R is a ribonucleotide residue and the consensus for lie is:Ro,R18R23=are absentR24,R38,R40,R41,R57,R72=are independently A or absent;R26,R65=are independently A,C or absent;R58,R59,R67=are independently N or absent; 190 WO 2024/216206 PCT/US2024/024492 R22= A,C,U or absent;R6,R9,R14,R15,R29,R34,R43,R46,R48,R50,R51,R63,R69=are independently A,G or absent;R37,R56=are independently A,G,U or absent; R54= A,U or absent;R28,R35,R60,R62,R71=are independently C or absent;R2,R52,R70=are independently C,G or absent; R5= C,G,U or absent;R3,R4,Rn,R13,R17,R21,R30,R42,R44,R45,R49,R53,R55,R61,R64,R66=are independently C,U or absent; R1,R10,R19,R20,R25,R27,R31,R68=are independently G or absent;R7,R!2,R32=are independently G,U or absent; R8,R16,R33,R36,R39=are independently U or absent; [R47] x = N or absent;wherein, e.g., x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-l l, x=l-10, x=10-271, x=20-271, x=30-271, x=40-271, x=50-271, x=60-271, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=l l, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.In an embodiment, a TREM disclosed herein comprises the sequence of Formula III ile (SEQIDNO: 591),Ro- R1-R2- R-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66־R67- R68-R69-R70-R71-Rwherein Risa ribonucleotide residue and the consensus for Ile is: 191 WO 2024/216206 PCT/US2024/024492 Ro,R18R23=are absentR14,R24,R38,R40,R41,R57,R72=are independently A or absent;R26,R65=are independently A,C or absent;R22,R59=are independently A,C,U or absent;R6,R9,R15,R34,R43,R46,R51,R56,R63,R69=are independently A,G or absent; R37= A,G,U or absent;R13,R28,R35,R44,R55,R60,R62,R71=are independently C or absent;R2,R5,R70=are independently C,G or absent;R58,R67=are independently C,G,U or absent;R3,R4,R11,R17,R21,R30,R42,R45,R49,R53,R61,R64,R66=are independently C,U or absent; R1,R1o,R19,R2o,R25,R27,R29,R31,R32,R48,R5o,R52,R68=are independently G or absent; R7,R12=are independently G,U or absent;R8,R16,R33,R36,R39,R54=are independently U or absent; [R47] x = N or absent;wherein, e.g., x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-ll, x=l-10, x=10-271, x=20-271, x=30-271, x=40-271, x=50-271, x=60-271, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=ll, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.Methionine TREM Consensus sequence In an embodiment, a TREM disclosed herein comprises the sequence of Formula 1 met(SEQ ID NO: 592),Ro- R1-R2- R3-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- 192 WO 2024/216206 PCT/US2024/024492 R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66־R67- R68-R69-R70-R71-R72wherein Risa ribonucleotide residue and the consensus for Met is:Ro,R23=are absent;R14,R38,R40,R57=are independently A or absent;R60= A,C or absent;R33,R48,R70=are independently A,C,G or absent;Rl,R3,R4,R5,R6,Rll,R12,R16,R17,R21,R22,R26,R27,R29,R30,R31,R32,R42,R44,R45,R46,R49,R50,R58,R2,R63,R66,R67,R68,R69,R71=are independently N or absent;R18,R35,R4!,R59,R65=are independently A,C,U or absent;R9,R15,R51=are independently A,G or absent;R7,R24,R25,R34,R53,R56=are independently A,G,U or absent;R72= A,U or absent;R37= C or absent;R10,R55=are independently C,G or absent; R2,R13,R28,R43,R64=are independently C,G,U or absent;R36,R61=are independently C,U or absent;R19,R20,R52=are independently G or absent;R8,R39,R54=are independently U or absent; [R47] x = N or absent;wherein, e.g, x=l-271 (e.g, x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x= 1 -12, x= 1 -11, x= 1 -10, x= 10-271, x=20-27 1, x=3 0-271, x=40-27 1, x=50-27 1, x=60-27 1, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=ll, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent. 193 WO 2024/216206 PCT/US2024/024492 In an embodiment, a TREM disclosed herein comprises the sequence of Formula 11 met (SEQ ID NO: 593),Ro- Rl- R2- R3-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48־R49־R50־R51־R52-R53־R54-R55־R56־R57־R58־R59-R60־R61־R62־R63־R64־R65־R66-R67־ R68-R69-R70-R71-R72wherein Risa ribonucleotide residue and the consensus for Met is:Ro,R18R22,R23=are absentR14,R24,R38,R40,R41,R57,R72=are independently A or absent;R59,R60,R62,R65=are independently A,C or absent;R6,R45,R67=are independently A,C,G or absent;R4= N or absent;R21,R42=are independently A,C,U or absent;R1,R9,R27,R29,R32,R46,R51=are independently A,G or absent;R17,R49,R53,R56,R58=are independently A,G,U or absent;R63=A,U or absent;R3,R13,R37=are independently C or absent;R48,R55,R64,R70=are independently C,G or absent;R2,R5,R66,R68=are independently C,G,U or absent;Ru,R16,R26,R28,R30,R31,R35,R36,R43,R44,R61,R71=are independently C,U or absent;R10,R12,R!5,R19,R20,R25,R33,R52,R69=are independently G or absent;R7,R34,R50=are independently G,U or absent;R8,R39,R54=are independently U or absent;[R47] x = N or absent;wherein, e.g., x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-l l, x=l-10, x=10-271, x=20-271, x=30-271, x=40-271, x=50-271, x=60-271, x=70- 194 WO 2024/216206 PCT/US2024/024492 271, x=80-271, x=l 00-271, x=l 25-271, x=l 50-271, x=l 75-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=ll, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.In an embodiment, a TREM disclosed herein comprises the sequence of Formula III met (SEQ ID NO: 594),Ro- R1-R2- R3-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41 -R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66־R67- R68-R69-R70-R71-R72wherein Risa ribonucleotide residue and the consensus for Met is:Ro,R18R22,R23=are absent R14,R24,R38,R40,R41,R57,R72=are independently A or absent;R59,R62,R65=are independently A,C or absent;R6,R67=are independently A,C,G or absent;R4,R2!=are independently A,C,U or absent;R1,R9,R27,R29,R32,R45,R46,R51=are independently A,G or absent;R17,R56,R58=are independently A,G,U or absent;R49,R53,R63=are independently A,U or absent;R3,R13,R26,R37,R43,R60=are independently C or absent;R2,R48,R55,R64,R70=are independently C,G or absent; R5,R66=are independently C,G,U or absent;Ru,R16,R28,R30,R31,R35,R36,R42,R44,R61,R71=are independently C,U or absent; R10,R12,R15,R!9,R20,R25,R33,R52,R69=are independently G or absent;R7,R34,R50,R68=are independently G,U or absent;R8,R39,R54=are independently U or absent; [R47] x = N or absent; 195 WO 2024/216206 PCT/US2024/024492 wherein, e.g., x=l-271 (e.g., x=1-250, x=l-225, x=l-200, x=1-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-ll, x=l-10, x= 10-271, x=20-271, x=3 0-271, x=40-271, x=50-271, x=60-271, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=l l, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.Leucine TREM Consensus sequence In an embodiment, a TREM disclosed herein comprises the sequence of Formula 1 leu(SEQ ID NO: 595),Ro- Rl- R2- R3-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66-R67- R68-R69-R70-R71-R72wherein Risa ribonucleotide residue and the consensus for Leu is:Ro=absent;R38,R57=are independently A or absent;R60= A,C or absent;R1,R13,R27,R48,R51,R56=are independently A,C,G or absent; R2,R3,R4,R5,R6,R7,R9,R10,Rll,R12,R16,R23,R26,R28,R29,R30,R31,R32,R33,R34,R37,R41,R42,R43,R44, R45,R46,R49,R50,R58,R62,R63,R65,R66,R67,R68,R69,R70=are independently N or absent;R17,R18,R21,R22,R25,R35,R55=are independently A,C,U or absent;R14,R15,R39,R72=are independently A,G or absent;R24,R40=are independently A,G,U or absent;R52,R61,R64,R71=are independently C,G,U or absent;R36,R53,R59=are independently C,U or absent; R19= G or absent;R2o= G,U or absent; 196 WO 2024/216206 PCT/US2024/024492 R8,R54=are independently U or absent; [R47] x = N or absent;wherein, e.g., x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-ll, x=l-10, x= 10-271, x=20-271, x=3 0-271, x=40-271, x=50-271, x=60-271, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=l l, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.In an embodiment, a TREM disclosed herein comprises the sequence of Formula II leu (SEQ ID NO: 596),Ro- Rl- R2- R3-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66-R67- R68-R69-R70-R71-R72wherein Risa ribonucleotide residue and the consensus for Leu is: Ro =absentR38,R57,R72=are independently A or absent;R60= A,C or absent; R4,R5,R48,R50,R56,R69=are independently A,C,G or absent;R6,R33,R41,R43,R46,R49,R58,R63,R66,R70=are independently N or absent; Ru,R12,R17,R21,R22,R28,R31,R37,R44,R55=are independently A,C,U or absent; R1,R9,R14,R15,R24,R27,R34,R39=are independently A,G or absent;R7,R29,R32,R40,R45=are independently A,G,U or absent;R25= A,U or absent;R13= C,G or absent;R2,R3,R!6,R26,R30,R52,R62,R64,R65,R67,R68=are independently C,G,U or absent; 197 WO 2024/216206 PCT/US2024/024492 R18,R35,R42,R53,R59,R61,R71=are independently C,U or absent;R19,R51=are independently G or absent;R10,R20=are independently G,U or absent;R8,R23,R36,R54=are independently U or absent; [R47] x = N or absent;wherein, e.g, x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x= 1 -12, x= 1 -11, x= 1 -10, x= 10-271, x=20-27 1, x=3 0-271, x=40-27 1, x=50-27 1, x=60-27 1, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=l l, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.In an embodiment, a TREM disclosed herein comprises the sequence of Formula III leu (SEQ ID NO: 597),Ro- R1-R2- R-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63־R64-R65-R66-R67- R68-R69-R70-R71-Rwherein Risa ribonucleotide residue and the consensus for Leu is:Ro =absentR38,R57,R72=are independently A or absent; R60= A,C or absent;R4,R5,R48,R50,R56,R58,R69=are independently A,C,G or absent; R6,R33,R43,R46,R49,R63,R66,R70=are independently N or absent; Ru,R12,R17,R21,R22,R28,R31,R37,R41,R44,R55=are independently A,C,U or absent; R1,R9,R14,R15,R24,R27,R34,R39=are independently A,G or absent;R7,R29,R32,R40,R45=are independently A,G,U or absent; 198 WO 2024/216206 PCT/US2024/024492 R25= A,U or absent;R13= C,G or absent;R2,R3,R16,R30,R52,R62,R64,R67,R68=are independently C,G,U or absent;R18,R35,R42,R53,R59,R61,R65,R71=are independently C,U or absent;R19,R51=are independently G or absent;R10,R20,R26=are independently G,U or absent;R8,R23,R36,R54=are independently U or absent; [R47] x = N or absent;wherein, e.g, x=l-271 (e.g, x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x= 1 -12, x= 1 -11, x= 1 -10, x= 10-271, x=20-27 1, x=3 0-271, x=40-27 1, x=50-27 1, x=60-27 1, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=ll, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.Lysine TREM Consensus sequenceIn an embodiment, a TREM disclosed herein comprises the sequence of Formula I lys (SEQ ID NO: 598),Ro- R1-R2- R-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63־R64-R65-R66-R67- R68-R69-R70-R71-Rwherein Risa ribonucleotide residue and the consensus for Lys is:Ro =absent R14= A or absent;R40,R41=are independently A,C or absent;R34,R43,R51=are independently A,C,G or absent; 199 WO 2024/216206 PCT/US2024/024492 R1,R2,R3,R4,R5,R6,R7,R1L,R12,R16,R21,R26,R3O,R31,R32,R44,R45,R46,R48,R49,R5O,R58,R62,R63,R65, R66,R67,R68,R69,R70=are independently N or absent;R13,R17,R59,R71=are independently A,C,U or absent;R9,R15,R19,R20,R25,R27,R52,R56=are independently A,G or absent;R24,R29,R72=are independently A,G,U or absent;R18,R57=are independently A,U or absent; R10,R33=are independently C,G or absent;R42,R61,R64=are independently C,G,U or absent;R28,R35,R36,R37,R53,R55,R60=are independently C,U or absent; R8,R22,R23,R38,R39,R54=are independently U or absent; [R47] x = N or absent;wherein, e.g, x=l-271 (e.g, x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-l 1, x=l-10, x= 10-271, x=20-271, x=3 0-271, x=40-271, x=50-271, x=60-271, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=ll, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.In an embodiment, a TREM disclosed herein comprises the sequence of Formula II lys (SEQ ID NO: 599),Ro- R1- R2- R3-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66־R67- R68-R69-R70-R71-R72wherein Risa ribonucleotide residue and the consensus for Lys is:Ro,R18,R23=are absent R14= A or absent; 200 WO 2024/216206 PCT/US2024/024492 R40,R41,R43=are independently A,C or absent;R3,R7=are independently A,C,G or absent;R1,R6,Rn,R31,R45,R48,R49,R63,R65,R66,R68=are independently N or absent;R2,R12,R13,R17,R44,R67,R71=are independently A,C,U or absent; R9,R15,R19,R20,R25,R27,R34,R50,R52,R56,R70,R72=are independently A,G or absent; R5,R24,R26,R29,R32,R46,R69=are independently A,G,U or absent; R57= A,U or absent;R10,R61=are independently C,G or absent;R4,R16,R21,R30,R58,R64=are independently C,G,U or absent;R28,R35,R36,R37,R42,R53,R55,R59,R60,R62=are independently C,U or absent;R33,R51=are independently G or absent;R8=G,U or absent;R22,R38,R39,R54=are independently U or absent; [R47] x = N or absent;wherein, e.g., x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-ll, x=l-10, x=10-271, x=20-271, x=30-271, x=40-271, x=50-271, x=60-271, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=ll, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.In an embodiment, a TREM disclosed herein comprises the sequence of Formula III lys (SEQ ID NO: 600),Ro- R1- R2- R3-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66־R67- R68-R69-R70-R71-R72 201 WO 2024/216206 PCT/US2024/024492 wherein Risa ribonucleotide residue and the consensus for Lys is:Ro,R18,R23=absentR9,R14,R34,R4!=are independently A or absent; R4o= A,C or absent;R1,R3,R7,R31=are independently A,C,G or absent;R48,R65,R68=are independently N or absent;R2,R13,R17,R44,R63,R66=are independently A,C,U or absent;R5,R15,R19,R20,R25,R27,R29,R50,R52,R56,R70,R72=are independently A,G or absent;R6,R24,R32,R49=are independently A,G,U or absent;R12,R26,R46,R57=are independently A,U or absent;Ru,R28,R35,R43=are independently C or absent;R10,R45,R61=are independently C,G or absent;R4,R21,R64=are independently C,G,U or absent;R37,R53,R55,R59,R60,R62,R67,R71=are independently C,U or absent;R33,R51=are independently G or absent;R8,R30,R58,R69=are independently G,U or absent; R16,R22,R36,R38,R39,R42,R54=are independently U or absent; [R47] x = N or absent;wherein, e.g., x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x= 1 -12, x= 1 -11, x= 1 -10, x= 10-271, x=20-27 1, x=3 0-271, x=40-27 1, x=50-27 1, x=60-27 1, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=l l, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent. 202 WO 2024/216206 PCT/US2024/024492 Phenylalanine TREM Consensus sequence In an embodiment, a TREM disclosed herein comprises the sequence of Formula 1 phe (SEQIDNO: 601),Ro- R1-R2- R-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66־R67- R68־R69-R70-R71־R72wherein Risa ribonucleotide residue and the consensus for Phe is:Ro,R23=are absentR9,R14,R38,R39,R57,R72=are independently A or absent;R?1= A,C or absent;R41,R70=are independently A,C,G or absent; R4,R5,R6,R3O,R31,R32,R34,R42,R44,R45,R46,R48,R49,R58,R62,R63,R66,R67,R68,R69=are independently N or absent;R16,R61,R65=are independently A,C,U or absent;R15,R26,R27,R29,R40,R56=are independently A,G or absent; R7,R51=are independently A,G,U or absent;R22,R24=are independently A,U or absent;R55,R60=are independently C or absent; R2,R3,R21,R33,R43,R50,R64=are independently C,G,U or absent;Ru,R12,R13,R17,R28,R35,R36,R59=are independently C,U or absent; R10,R19,R20,R25,R37,R52=are independently G or absent;R1= G,U or absent;R8,R18,R53,R54=are independently U or absent; [R47] x = N or absent;wherein, e.g., x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-l l, x=l-10, x=10-271, x=20-271, x=30-271, x=40-271, x=50-271, x=60-271, x=70- 203 WO 2024/216206 PCT/US2024/024492 271, x=80-271, x=l 00-271, x=l 25-271, x=l 50-271, x=l 75-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=ll, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.In an embodiment, a TREM disclosed herein comprises the sequence of Formula II phe (SEQ ID NO: 602),Ro- Ri- R2- R3-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41 -R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66־R67- R68-R69-R70-R71-R72wherein Risa ribonucleotide residue and the consensus for Phe is:R0,R18,R23=absentR14,R24,R38,R39,R57,R72=are independently A or absent; R46,R71=are independently A,C or absent;R4,R70=are independently A,C,G or absent; R45= A,C,U or absent;R6,R7,R15,R26,R27,R32,R34,R40,R41,R56,R69=are independently A,G or absent; R29= A,G,U or absent;R5,R9,R67=are independently A,U or absent;R35,R49,R55,R60=are independently C or absent;R21,R43,R62=are independently C,G or absent; R2,R33,R68=are independently C,G,U or absent;R3,Rn,R12,R13,R28,R30,R36,R42,R44,R48,R58,R59,R61,R66=are independently C,U or absent; R10,R!9,R20,R25,R37,R51,R52,R63,R64=are independently G or absent;R1,R31,R50=are independently G,U or absent;R8,R16,R17,R22,R53,R54,R65=are independently U or absent; [R47] x = N or absent; 204 WO 2024/216206 PCT/US2024/024492 wherein, e.g., x=l-271 (e.g., x=1-250, x=l-225, x=l-200, x=1-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-ll, x=l-10, x= 10-271, x=20-271, x=3 0-271, x=40-271, x=50-271, x=60-271, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=l l, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.In an embodiment, a TREM disclosed herein comprises the sequence of Formula III phe (SEQ ID NO: 603),Ro- R1-R2- Ra-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66־R67- R68-R69-R70-R71-R72wherein Risa ribonucleotide residue and the consensus for Phe is:Ro R18 R22 R23=ab sentR5,R7,R14,R24,R26,R32,R34,R38,R39,R41,R57,R72=are independently A or absent; R46= A,C or absent;R70= A,C,G or absent;R4,R6,R15,R56,R69=are independently A,G or absent;R9,R45=are independently A,U or absent;R2,R11,R13,R35,R43,R49,R55,R60,R68,R71=are independently C or absent; R33= C,G or absent;R3,R28,R36,R48,R58,R59,R61=are independently C,U or absent;R1,R10,R19,R20,R21,R25,R27,R29,R37,R40,R51,R52,R62,R63,R64=are independently G or absent; R8,R12,R16,R17,R30,R31,R42,R44,R50,R53,R54,R65,R66,R67=are independently U or absent; [R47] x = N or absent; 205 WO 2024/216206 PCT/US2024/024492 wherein, e.g., x=l-271 (e.g., x=1-250, x=l-225, x=l-200, x=1-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-ll, x=l-10, x= 10-271, x=20-271, x=3 0-271, x=40-271, x=50-271, x=60-271, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=l l, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.Proline TREM Consensus sequence In an embodiment, a TREM disclosed herein comprises the sequence of Formula 1 pro(SEQ ID NO: 604),Ro- Rl- R2- R3-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66-R67- R68-R69-R70-R71-R72wherein Risa ribonucleotide residue and the consensus for Pro is:Ro =absentR14,R57=are independently A or absent;R70,R72=are independently A,C or absent;R9,R26,R27=are independently A,C,G or absent; R4,R5,R6,R16,R21,R29,R30,R31,R32,R33,R34,R37,R41,R42,R43,R44,R45,R46,R48,R49,R50,R58,R61,R62, R63,R64,R66,R67,R68=are independently N or absent;R35,R65=are independently A,C,U or absent;R24,R40,R56=are independently A,G or absent;R7,R25,R5!=are independently A,G,U or absent;R55,R60=are independently C or absent;R1,R3,R71=are independently C,G or absent;Ru,R12,R20,R69=are independently C,G,U or absent;R13,R17,R18,R22,R23,R28,R59=are independently C,U or absent; 206 WO 2024/216206 PCT/US2024/024492 R10,R15,R19,R38,R39,R52=are independently G or absent;R2= are independently G,U or absent;R8,R36,R53,R54=are independently U or absent; [R47] x = N or absent;wherein, e.g., x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-l l, x=l-10, x=10-271, x=20-271, x=30-271, x=40-271, x=50-271, x=60-271, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=ll, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.In an embodiment, a TREM disclosed herein comprises the sequence of Formula II pro (SEQ ID NO: 605),Ro- Ri- R2- R3-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66-R67- R68-R69-R70-R71 -Rwherein Risa ribonucleotide residue and the consensus for Pro is:Ro Ri 7 Ri 8 R22 R23=ab sent;R14,R45,R56,R57,R58,R65,R68=are independently A or absent; R61= A,C,G or absent;R43=N or absent; R37= A, C,U or absent;R24,R27,R33,R40,R44,R63=are independently A,G or absent;R3,R12,R30,R32,R48,R55,R60,R70,R71,R72=are independently C or absent;R5,R34,R42,R66=are independently C,G or absent; R2o= C,G,U or absent; 207 WO 2024/216206 PCT/US2024/024492 R35,R41,R49,R62=are independently C,U or absent;R1,R2,R6,R9,R10,R15,R19,R26,R38,R39,R46,R50,R51,R52,R64,R67,R69=are independently G or absent; Rn,R16=are independently G,U or absent;R4,R7,R8,R13,R21,R25,R28,R29,R31,R36,R53,R54,R59=are independently U or absent; [R47] x = N or absent;wherein, e.g., x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-l 1, x=l-10, x= 10-271, x=20-271, x=3 0-271, x=40-271, x=50-271, x=60-271, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=ll, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.In an embodiment, a TREM disclosed herein comprises the sequence of Formula III pro (SEQ ID NO: 606),Ro- R1-R2- R3-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31 -R32-R33-R34-R35-R36-R37-R38-R39-R40-R41 -R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66־R67- R68-R69-R70-R71-R72wherein Risa ribonucleotide residue and the consensus for Pro is:Ro Ri 7 Ri 8 R22 R23=ab sentR14,R45,R56,R57,R58,R65,R68=are independently A or absent; R37= A,C,U or absent;R24,R27,R40=are independently A,G or absent;R3,R5,R12,R30,R32,R48,R49,R55,R60,R61,R62,R66,R70,R71,R72=are independently C or absent; R34,R42=are independently C,G or absent; R43= C,G,U or absent; 208 WO 2024/216206 PCT/US2024/024492 R41= C,U or absent;Rl,R2,R6,R9,RlO,R15,R19,R2O,R26,R33,R38,R39,R44,R46,R5O,R51,R52,R63,R64,R67,R69=are independently G or absent;R16= G,U or absent;R4,R7,R8,R11,R13,R21,R25,R28,R29,R31,R35,R36,R53,R54,R59=are independently U or absent; [R47] x = N or absent; wherein, e.g., x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-l 1, x=l-10, x= 10-271, x=20-271, x=3 0-271, x=40-271, x=50-271, x=60-271, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=ll, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.Serine TREM Consensus sequence In an embodiment, a TREM disclosed herein comprises the sequence of Formula 1 ser(SEQ ID NO: 607),Ro- R1-R2- R3-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66־R67- R68-R69-R70-R71-Rwherein Risa ribonucleotide residue and the consensus for Ser is:Ro=absent;R14,R24,R57=are independently A or absent; R41= A,C or absent;R2,R3,R4,R5,R6,R7,R9,R10,Rll,R12,R13,R16,R21,R25,R26,R27,R28,R30,R31,R32,R33,R34,R37,R42,R43, R44,R45,R46,R48,R49,R50,R62,R63,R64,R65,R66,R67,R68,R69,R70=are independently N or absent; R18= A,C,U or absent;R15,R40,R5!,R56=are independently A,G or absent; 209 WO 2024/216206 PCT/US2024/024492 R1,R29,R58,R72=are independently A,G,U or absent; R39= A,U or absent;R6o= C or absent;R38= C,G or absent;R17,R22,R23,R71=are independently C,G,U or absent;R8,R35,R36,R55,R59,R6!=are independently C,U or absent;R19,R20=are independently G or absent; R52= G,U or absent;R53,R54=are independently U or absent; [R47] x = N or absent;wherein, e.g., x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x= 1 -12, x= 1 -11, x= 1 -10, x= 10-271, x=20-27 1, x=3 0-271, x=40-27 1, x=50-27 1, x=60-27 1, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=l l, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.In an embodiment, a TREM disclosed herein comprises the sequence of Formula II ser (SEQ ID NO: 608),Ro- Rl- R2- R3-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66-R67- R68-R69-R70-R71-Rwherein Risa ribonucleotide residue and the consensus for Ser is:Ro,R23=absentR14,R24,R41,R57=are independently A or absent; R44= A,C or absent; 210 WO 2024/216206 PCT/US2024/024492 R25,R45,R48=are independently A,C,G or absent;R2,R3,R4,R5,R37,R50,R62,R66,R67,R69,R70=are independently N or absent;R12,R28,R65=are independently A,C,U or absent;R9,R15,R29,R34,R40,R56,R63=are independently A,G or absent;R7,R26,R30,R33,R46,R58,R72=are independently A,G,U or absent; R39= A,U or absent;Ru,R35,R60,R61=are independently C or absent;R13,R38=are independently C,G or absent;R6,R17,R31,R43,R64,R68=are independently C,G,U or absent;R36,R42,R49,R55,R59,R71=are independently C,U or absent;R10,R19,R20,R27,R51=are independently G or absent;R1,R16,R32,R52=are independently G,U or absent;R8,R18,R21,R22,R53,R54=are independently U or absent; [R47] x = N or absent;wherein, e.g., x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-ll, x=l-10, x=10-271, x=20-271, x=30-271, x=40-271, x=50-271, x=60-271, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=ll, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.In an embodiment, a TREM disclosed herein comprises the sequence of Formula III ser (SEQ ID NO: 609),Ro- R1- R2- R3-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66־R67- R68-R69-R70-R71-R72 211 WO 2024/216206 PCT/US2024/024492 wherein Risa ribonucleotide residue and the consensus for Ser is:Ro,R23=absentR14,R24,R41,R57,R58=are independently A or absent; R44= A,C or absent;R25,R48=are independently A,C,G or absent;R2,R3,R5,R37,R66,R67,R69,R70=are independently N or absent;R12,R28,R62=are independently A,C,U or absent;R7,R9,R15,R29,R33,R34,R40,R45,R56,R63=are independently A,G or absent;R4,R26,R46,R50=are independently A,G,U or absent;R30,R39=are independently A,U or absent;Ru,R17,R35,R60,R61=are independently C or absent;R13,R38=are independently C,G or absent;R6,R64=are independently C,G,U or absent;R31,R42,R43,R49,R55,R59,R65,R68,R71=are independently C,U or absent;R10,R19,R20,R27,R51,R52=are independently G or absent;R1,R16,R32,R72=are independently G,U or absent; R8,R18,R21,R22,R36,R53,R54=are independently U or absent; [R47] x = N or absent;wherein, e.g., x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x= 1 -12, x= 1 -11, x= 1 -10, x= 10-271, x=20-27 1, x=3 0-271, x=40-27 1, x=50-27 1, x=60-27 1, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=l l, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent. 212 WO 2024/216206 PCT/US2024/024492 Threonine TREM Consensus sequenceIn an embodiment, a TREM disclosed herein comprises the sequence of Formula 1 thr(SEQ ID NO: 610), Ro- Ri- R2- R3-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x־R48־R49־R50־R51־R52־R53־R54-R55־R56־R57־R58־R59־R60־R61־R62־R63־R64־R65־R66־R67־ R68-R69-R70-R71-R72wherein Risa ribonucleotide residue and the consensus for Thr is:Ro,R23=absentR14,R41,R57=are independently A or absent;R56,R70=are independently A,C,G or absent; R4,R5,R6,R7,R12,R16,R26,R3O,R31,R32,R34,R37,R42,R44,R45,R46,R48,R49,R5O,R58,R62,R63,R64,R65,R 66,R67,R68,R72=are independently N or absent;R13,R17,R2!,R35,R61=are independently A,C,U or absent; R1,R9,R24,R27,R29,R69=are independently A,G or absent;R15,R25,R51=are independently A,G,U or absent;R40,R53=are independently A,U or absent; R33,R43=are independently C,G or absent;R2,R3,R59=are independently C,G,U or absent;Ru,R18,R22,R28,R36,R54,R55,R60,R71=are independently C,U or absent; R10,R20,R38,R52=are independently G or absent;R19= G,U or absent; R8,R39=are independently U or absent;[R47] x = N or absent;wherein, e.g, x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x= 1 -12, x= 1 -11, x= 1 -10, x= 10-271, x=20-27 1, x=3 0-271, x=40-27 1, x=50-27 1, x=60-27 1, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=ll, x=12, x=13, x=14, x=15, x=16, x=17, 213 WO 2024/216206 PCT/US2024/024492 x=1 8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.In an embodiment, a TREM disclosed herein comprises the sequence of Formula II thr (SEQIDNO: 611),Ro- Ri- R2- R3-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48־R49־R50-R51־R52-R53־R54-R55־R56־R57-R58־R59-R60־R61־R62־R63־R64-R65־R66-R67־ R68-R69-R70-R71 -R72wherein Risa ribonucleotide residue and the consensus for Thr is:Ro,R18R23=absent R14,R41,R57=are independently A or absent;R9,R42,R44,R48,R56,R70=are independently A,C,G or absent; R4,R6,R12,R26,R49,R58,R63,R64,R66,R68=are independently N or absent;R13,R21,R31,R37,R62=are independently A,C,U or absent; R1,R!5,R24,R27,R29,R46,R51,R69=are independently A,G or absent; R7,R25,R45,R50,R67=are independently A,G,U or absent;R40,R53=are independently A,U or absent; R35= C or absent;R33,R43=are independently C,G or absent;R2,R3,R5,R16,R32,R34,R59,R65,R72=are independently C,G,U or absent; R11,R17,R22,R28,R30,R36,R55,R60,R61,R71=are independently C,U or absent;R10,R19,R20,R38,R52=are independently G or absent;R8,R39,R54=are independently U or absent; [R47] x = N or absent;wherein, e.g., x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x= 1 -12, x= 1 -11, x= 1 -10, x= 10-271, x=20-27 1, x=3 0-271, x=40-27 1, x=50-27 1, x=60-27 1, x=70- 214 WO 2024/216206 PCT/US2024/024492 271, x=80-271, x=l 00-271, x=l 25-271, x=l 50-271, x=l 75-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=ll, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.In an embodiment, a TREM disclosed herein comprises the sequence of Formula III tiir (SEQIDNO: 612),Ro- R1-R2- R3-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41 -R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66־R67- R68-R69-R70-R71-R72wherein Risa ribonucleotide residue and the consensus for Thr is:Ro,R18,R23=absent R14,R40,R41,R57=are independently A or absent; R44= A,C or absent;R9,R42,R48,R56=are independently A,C,G or absent;R4,R6,R!2,R26,R58,R64,R66,R68=are independently N or absent;R13,R21,R31,R37,R49,R62=are independently A,C,U or absent; R1,R15,R24,R27,R29,R46,R51,R69=are independently A,G or absent; R7,R25,R45,R50,R63,R67=are independently A,G,U or absent; R53= A,U or absent;R35= C or absent;R2,R33,R43,R70=are independently C,G or absent;R5,R!6,R34,R59,R65=are independently C,G,U or absent;R3,R11,R22,R28,R30,R36,R55,R60,R61,R71=are independently C,U or absent; R10,R19,R20,R38,R52=are independently G or absent; R32= G,U or absent;R8,R17,R39,R54,R72=are independently U or absent; [R47] x = N or absent;215 WO 2024/216206 PCT/US2024/024492 wherein, e.g., x=l-271 (e.g., x=1-250, x=l-225, x=l-200, x=1-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-ll, x=l-10, x= 10-271, x=20-271, x=3 0-271, x=40-271, x=50-271, x=60-271, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=l l, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.Tryptophan TREM Consensus sequence In an embodiment, a TREM disclosed herein comprises the sequence of Formula 1 trp (SEQ ID NO: 613),Ro- R1-R2- R-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66-R67- R68-R69-R70-R71-R72wherein Risa ribonucleotide residue and the consensus for Trp is:Ro= absent;R24,R39,R41,R57=are independently A or absent;R2,R3,R26,R27,R40,R48=are independently A,C,G or absent;R4,R5,R6,R29,R30,R31,R32,R34,R42,R44,R45,R46,R49,R51,R58,R63,R66,R67,R68=are independently N or absent;R13,R14,R!6,R18,R21,R61,R65,R71=are independently A,C,U or absent; R1,R9,R10,R15,R33,R50,R56=are independently A,G or absent;R7,R25,R72=are independently A,G,U or absent;R37,R38,R55,R60=are independently C or absent;R12,R35,R43,R64,R69,R70=are independently C,G,U or absent;Ru,R17,R22,R28,R59,R62=are independently C,U or absent;R19,R20,R52=are independently G or absent; R8,R23,R36,R53,R54=are independently U or absent; 216 WO 2024/216206 PCT/US2024/024492 [R47] x = N or absent;wherein, e.g, x=l-271 (e.g, x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-l 1, x=l-10, x= 10-271, x=20-271, x=3 0-271, x=40-271, x=50-271, x=60-271, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=ll, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.In an embodiment, a TREM disclosed herein comprises the sequence of Formula II trp (SEQIDNO: 614),Ro- R1- R2- R3-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66־R67- R68-R69-R70-R71-R72wherein Risa ribonucleotide residue and the consensus for Trp is:Ro R18 R22 R23=ab sentR14,R24,R39,R41,R57,R72=are independently A or absent;R3,R4,R13,R61,R71=are independently A,C or absent;R6,R44=are independently A,C,G or absent; R21= A,C,U or absent;R2,R7,R15,R25,R33,R34,R45,R56,R63=are independently A,G or absent; R58= A,G,U or absent;R46= A,U or absent;R37,R38,R55,R60,R62=are independently C or absent;R12,R26,R27,R35,R40,R48,R67=are independently C,G or absent;R32,R43,R68=are independently C,G,U or absent;R11,R16,R28,R31,R49,R59,R65,R70=are independently C,U or absent; 217 WO 2024/216206 PCT/US2024/024492 R1,R9,R10,R19,R20,R50,R52,R69=are independently G or absent;R5,R8,R29,R30,R42,R51,R64,R66=are independently G,U or absent;R17,R36,R53,R54=are independently U or absent; [R47] x = N or absent;wherein, e.g., x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-l l, x=l-10, x=10-271, x=20-271, x=30-271, x=40-271, x=50-271, x=60-271, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=ll, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.

In an embodiment, a TREM disclosed herein comprises the sequence of Formula III trp (SEQIDNO: 615),Ro- R1-R2- R-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63־R64-R65-R66-R67- R68-R69-R70-R71-R72wherein Risa ribonucleotide residue and the consensus for Trp is:R0R18R22R23=absent R14,R24,R39,R41,R57,R72=are independently A or absent;R3,R4,R!3,R61,R71=are independently A,C or absent; R6,R44=are independently A,C,G or absent;R2!= A,C,U or absent;R2,R7,R!5,R25,R33,R34,R45,R56,R63=are independently A,G or absent;R58= A,G,U or absent;R46= A,U or absent; 218 WO 2024/216206 PCT/US2024/024492 R37,R38,R55,R60,R62=are independently C or absent;R12,R26,R27,R35,R40,R48,R67=are independently C,G or absent;R32,R43,R68=are independently C,G,U or absent;R11,R16,R28,R31,R49,R59,R65,R70=are independently C,U or absent;R1,R9,R10,R19,R20,R50,R52,R69=are independently G or absent;R5,R8,R29,R30,R42,R51,R64,R66=are independently G,U or absent;R17,R36,R53,R54=are independently U or absent; [R47] x = N or absent;wherein, e.g, x=l-271 (e.g, x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x= 1 -12, x= 1 -11, x= 1 -10, x= 10-271, x=20-27 1, x=3 0-271, x=40-27 1, x=50-27 1, x=60-27 1, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=ll, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.Tyrosine TREM Consensus sequence In an embodiment, a TREM disclosed herein comprises the sequence of Formula 1 tyr (SEQ ID NO: 616),Ro- R1-R2- R-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63־R64-R65-R66-R67- R68-R69-R70-R71-Rwherein Risa ribonucleotide residue and the consensus for Tyr is:Ro =absentR14,R39,R57=are independently A or absent;R41,R48,R51,R71=are independently A,C,G or absent; R3,R4,R5,R6,R9,R1O,R12,R13,R16,R25,R26,R3O,R31,R32,R42,R44,R45,R46,R49,R5O,R58,R62,R63,R66, R67,R68,R69,R70=are independently N or absent; 219 WO 2024/216206 PCT/US2024/024492 R22,R65=are independently A,C,U or absent;R15,R24,R27,R33,R37,R40,R56=are independently A,G or absent;R7,R29,R34,R72=are independently A,G,U or absent;R23,R53=are independently A,U or absent;R35,R60=are independently C or absent; R20= C,G or absent;R1,R2,R28,R61,R64=are independently C,G,U or absent;Ru,R17,R21,R43,R55=are independently C,U or absent;R19,R52=are independently G or absent;R8,R18,R36,R38,R54,R59=are independently U or absent; [R47] x = N or absent;wherein, e.g., x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-l 1, x=l-10, x= 10-271, x=20-271, x=3 0-271, x=40-271, x=50-271, x=60-271, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=ll, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.In an embodiment, a TREM disclosed herein comprises the sequence of Formula II tyr (SEQIDNO: 617),Ro- R1-R2- R3-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31 -R32-R33-R34-R35-R36-R37-R38-R39-R40-R41 -R42- R43- R44-R45- R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66־R67- R68-R69-R70-R71-R72wherein Risa ribonucleotide residue and the consensus for Tyr is:Ro,R18,R23=absentR7,R9,R14,R24,R26,R34,R39,R57=are independently A or absent; 220 WO 2024/216206 PCT/US2024/024492 R44,R69=are independently A,C or absent; R71= A,C,G or absent;R68= N or absent;R58= A,C,U or absent;R33,R37,R41,R56,R62,R63=are independently A,G or absent;R6,R29,R72=are independently A,G,U or absent;R31,R45,R53=are independently A,U or absent; R13,R35,R49,R60=are independently C or absent;R20,R48,R64,R67,R70=are independently C,G or absent;R1,R2,R5,R16,R66=are independently C,G,U or absent;Ru,R21,R28,R43,R55,R61=are independently C,U or absent; R10,R15,R19,R25,R27,R40,R51,R52=are independently G or absent; R3,R4,R30,R32,R42,R46=are independently G,U or absent;R8,R12,R17,R22,R36,R38,R50,R54,R59,R65=are independently U or absent; [R47] x = N or absent;wherein, e.g., x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-ll, x=l-10, x= 10-271, x=20-271, x=3 0-271, x=40-271, x=50-271, x=60-271, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=l l, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, orx=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.In an embodiment, a TREM disclosed herein comprises the sequence of Formula III tyr (SEQIDNO: 618),Ro- R1-R2- Ra-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- 221 WO 2024/216206 PCT/US2024/024492 R46- [R47]x-R48-R49-R50-R51-R52-R53-R54-R55-R56-R57-R58-R59-R60-R61-R62-R63-R64-R65-R66־R67- R68-R69-R70-R71-R72wherein Risa ribonucleotide residue and the consensus for Tyr is:Ro Ri 8,R23=ab sentR7,R9,R14,R24,R26,R34,R39,R57,R72=are independently A or absent;R44,R69=are independently A,C or absent; R71= A,C,G or absent;R37,R41,R56,R62,R63=are independently A,G or absent;R6,R29,R68=are independently A,G,U or absent;R31,R45,R58=are independently A,U or absent;R13,R28,R35,R49,R60,R61=are independently C or absent;R5,R48,R64,R67,R70=are independently C,G or absent;R1,R2=are independently C,G,U or absent;R11,R16,R21,R43,R55,R66=are independently C,U or absent;R10,R15,R!9,R20,R25,R27,R33,R40,R51,R52=are independently G or absent;R3,R4,R30,R32,R42,R46=are independently G,U or absent;R8,R12,R17,R22,R36,R38,R50,R53,R54,R59,R65=are independently U or absent; [R47] x = N or absent;wherein, e.g., x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-l l, x=l-10, x=10-271, x=20-271, x=30-271, x=40-271, x=50-271, x=60-271, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=ll, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent. 222 WO 2024/216206 PCT/US2024/024492 Valine TREM Consensus sequenceIn an embodiment, a TREM disclosed herein comprises the sequence of Formula 1 val(SEQ ID NO: 619),Ro- Ri- R2- R3-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x־R48־R49־R50־R51־R52־R53־R54-R55־R56־R57־R58־R59־R60־R61־R62־R63־R64־R65־R66־R67־ R68-R69-R70-R71-R72wherein Risa ribonucleotide residue and the consensus for Val is:Ro,R23=absent;R24,R38,R57=are independently A or absent;R9,R72=are independently A,C,G or absent; R2,R4,R5,R6,R7,R12,R15,R16,R21,R25,R26,R29,R31,R32,R33,R34,R37,R41,R42,R43,R44,R45,R46,R48,R9,R50,R58,R61,R62,R63,R64,R65,R66,R67,R68,R69,R70=are independently N or absent;R17,R35,R59=are independently A,C,U or absent; R10,R14,R27,R40,R52,R56=are independently A,G or absent;R1,R3,R51,R53=are independently A,G,U or absent;R39= C or absent; R13,R30,R55=are independently C,G,U or absent;Ru,R22,R28,R60,R71=are independently C,U or absent;R19= G or absent; R20= G ,U or absent;R8,R18,R36,R54=are independently U or absent; [R47] x = N or absent;wherein, e.g., x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-l l, x=l-10, x=10-271, x=20-271, x=30-271, x=40-271, x=50-271, x=60-271, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=ll, x=12, x=13, x=14, x=15, x=16, x=17, 223 WO 2024/216206 PCT/US2024/024492 x=1 8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=l 10, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.In an embodiment, a TREM disclosed herein comprises the sequence of Formula II val (SEQ ID NO: 620),Ro- Ri- R2- R3-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48־R49־R50-R51־R52-R53־R54-R55־R56־R57-R58־R59-R60־R61־R62־R63־R64-R65־R66-R67־ R68-R69-R70-R71 -R72wherein Risa ribonucleotide residue and the consensus for Val is:Ro,R18R23=absent;R24,R38,R57=are independently A or absent;R64,R70,R72=are independently A,C,G or absent; R15,R16,R26,R29,R31,R32,R43,R44,R45,R49,R50,R58,R62,R65=are independently N or absent; R6,R17,R34,R37,R4!,R59=are independently A,C,U or absent;R9,R10,R14,R27,R40,R46,R51,R52,R56=are independently A,G or absent; R7,R12,R25,R33,R53,R63,R66,R68=are independently A,G,U or absent; R69= A,U or absent; R39= C or absent;R5,R67=are independently C,G or absent;R2,R4,R!3,R48,R55,R61=are independently C,G,U or absent; R11,R22,R28,R30,R35,R60,R71=are independently C,U or absent;R19= G or absent;R1,R3,R20,R42=are independently G,U or absent;R8,R21,R36,R54=are independently U or absent; [R47] x = N or absent;wherein, e.g., x=l-271 (e.g., x=l-250, x=l-225, x=l-200, x=l-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, 224 WO 2024/216206 PCT/US2024/024492 x=1-12, x=l-ll, x=l-10, x=l 0-271, x=20-271, x=30-271, x=40-271, x=50-271, x=60-271, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=l l, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.In an embodiment, a TREM disclosed herein comprises the sequence of Formula III val (SEQ ID NO: 621),Ro- R1-R2- R-R4 -R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22- R23-R24-R25-R26-R27-R28-R29-R30-R31-R32-R33-R34-R35-R36-R37-R38-R39-R40-R41-R42- R43- R44-R45- R46- [R47]x-R48־R49־R50־R51־R52-R53־R54-R55־R56־R57־R58־R59-R60־R61־R62־R63־R64־R65־R66-R67־ R68-R69-R70-R71 -Rwherein Risa ribonucleotide residue and the consensus for Val is:Ro,R18,R23=absent R24,R38,R40,R57,R72=are independently A or absent;R29,R64,R70=are independently A,C,G or absent;R49,R50,R62=are independently N or absent;R16,R26,R31,R32,R37,R41,R43,R59,R65=are independently A,C,U or absent; R9,R14,R27,R46,R52,R56,R66=are independently A,G or absent; R7,R12,R25,R33,R44,R45,R53,R58,R63,R68=are independently A,G,U or absent; R69= A,U or absent;R39= C or absent;R5,R67=are independently C,G or absent;R2,R4,R!3,R15,R48,R55=are independently C,G,U or absent; R6,R11,R22,R28,R30,R34,R35,R60,R61,R71=are independently C,U or absent; R10,R19,R5!=are independently G or absent;R1,R3,R20,R42=are independently G,U or absent; R8,R17,R21,R36,R54=are independently U or absent; [R47] x = N or absent; 225 WO 2024/216206 PCT/US2024/024492 wherein, e.g., x=l-271 (e.g., x=1-250, x=l-225, x=l-200, x=1-175, x=l-150, x=l-125, x=l-100, x=l-75, x=l-50, x=l-40, x=l-30, x=l-29, x=l-28, x=l-27, x=l-26, x=l-25, x=l-24, x=l-23, x=l-22, x=l-21, x=l-20, x=l-19, x=l-18, x=l-17, x=l-16, x=l-15, x=l-14, x=l-13, x=l-12, x=l-ll, x=l-10, x= 10-271, x=20-271, x=3 0-271, x=40-271, x=50-271, x=60-271, x=70- 271, x=80-271, x=100-271, x=125-271, x=150-271, x=175-271, x=200-271, x=225-271, x=l, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=l l, x=12, x=13, x=14, x=15, x=16, x=17, x=18, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271), provided that the TREM has one or both of the following properties: no more than 15% of the residues are N; or no more than 20 residues are absent.Variable region consensus sequenceIn an embodiment, a TREM disclosed herein comprises a variable region at position R47. In an embodiment, the variable region is 1-271 ribonucleotides in length (e.g. 1-250, 1-225, 1- 200, 1-175, 1-150, 1-125, 1-100, 1-75, 1-50, 1-40, 1-30, 1-29, 1-28, 1-27, 1-26, 1-25, 1-24, 1-23, 1-22, 1-21, 1-20, 1-19, 1-18, 1-17, 1-16, 1-15, 1-14, 1-13, 1-12, 1-11, 1-10, 10-271, 20-271, 30- 271, 40-271, 50-271, 60-271, 70-271, 80-271, 100-271, 125-271, 150-271, 175-271, 200-271, 225-271, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 60, 70, 80, 90, 100, 110, 125, 150, 175, 200, 225, 250, or 2ribonucleotides). In an embodiment, the variable region comprises any one, all or a combination of Adenine, Cytosine, Guanine or Uracil.In an embodiment, the variable region comprises a ribonucleic acid (RNA) sequence encoded by a deoxyribonucleic acid (DNA) sequence disclosed in Table 4, e.g., any one of SEQ ID NOs: 452-561 disclosed in Table 4. Table 4:Exemplary variable region sequences.

SEQ ID NO SEQUENCE 452 AAAATATAAATATATTTC453 AAGCT454 AAGTT455 AATTCTTCGGAATGT456 AGA457 AGTCC458 CAACC459 CAATC460 CAGC 226 WO 2024/216206 PCT/US2024/024492 461 CAGGCGGGTTCTGCCCGCGC462 CATACCTGCAAGGGTATC463 CGACCGCAAGGTTGT464 CGACCTTGCGGTCAT465 CGATGCTAATCACATCGT466 CGATGGTGACATCAT467 CGATGGTTTACATCGT468 CGCCGTAAGGTGT469 CGCCTTAGGTGT470 CGCCTTTCGACGCGT471 CGCTTCACGGCGT472 CGGCAGCAATGCTGT473 CGGCTCCGCCTTC474 CGGGTATCACAGGGTC475 CGGTGCGCAAGCGCTGT476 CGTACGGGTGACCGTACC477 CGTCAAAGACTTC478 CGTCGTAAGACTT479 CGTTGAATAAACGT480 CTGTC481 GGCC482 GGGGATT483 GGTC484 GGTTT485 GTAG486 TAACTAGATACTTTCAGAT487 TACTCGTATGGGTGC488 TACTTTGCGGTGT489 TAGGCGAGTAACATCGTGC490 TAGGCGTGAATAGCGCCTC491 TAGGTCGCGAGAGCGGCGC492 TAGGTCGCGTAAGCGGCGC493 TAGGTGGTTATCCACGC494 TAGTC495 TAGTT496 TATACGTGAAAGCGTATC497 TATAGGGTCAAAAACTCTATC498 TATGCAGAAATACCTGCATC499 TCCCCATACGGGGGC500 TCCCGAAGGGGTTC501 TCTACGTATGTGGGC502 TCTCATAGGAGTTC503 TCTCCTCTGGAGGC 227 WO 2024/216206 PCT/US2024/024492 53 504 TCTTAGCAATAAGGT505 TCTTGTAGGAGTTC506 TGAACGTAAGTTCGC507 TGAACTGCGAGGTTCC508 TGAC509 TGACCGAAAGGTCGT510 TGACCGCAAGGTCGT511 TGAGCTCTGCTCTC512 TGAGGCCTCACGGCCTAC513 TGAGGGCAACTTCGT514 TGAGGGTCATACCTCC515 TGAGGGTGCAAATCCTCC516 TGCCGAAAGGCGT517 TGCCGTAAGGCGT518 TGCGGTCTCCGCGC519 TGCTAGAGCAT520 TGCTCGTATAGAGCTC521 TGGACAATTGTCTGC522 TGGACAGATGTCCGT523 TGGACAGGTGTCCGC524 TGGACGGTTGTCCGC525 TGGACTTGTGGTC526 TGGAGATTCTCTCCGC527 TGGCATAGGCCTGC528 TGGCTTATGTCTAC529 TGGGAGTTAATCCCGT530 TGGGATCTTCCCGC531 TGGGCAGAAATGTCTC532 TGGGCGTTCGCCCGC533 TGGGCTTCGCCCGC534 TGGGGGATAACCCCGT535 TGGGGGTTTCCCCGT536 TGGT537 TGGTGGCAACACCGT538 TGGTTTATAGCCGT539 TGTACGGTAATACCGTACC540 TGTCCGCAAGGACGT541 TGTCCTAACGGACGT542 TGTCCTATTAACGGACGT543 TGTCCTTCACGGGCGT544 TGTCTTAGGACGT545 TGTGCGTTAACGCGTACC546 TGTGTCGCAAGGCACC 228 WO 2024/216206 PCT/US2024/024492 96 547 TGTTCGTAAGGACTT548 TTCACAGAAATGTGTC549 TTCCCTCGTGGAGT550 TTCCCTCTGGGAGC100 551 TTCCCTTGTGGATC101 552 TTCCTTCGGGAGC102 553 TTCTAGCAATAGAGT103 554 TTCTCCACTGGGGAGC104 555 TTCTCGAGAGGGAGC105 556 TTCTCGTATGAGAGC106 557 TTT AAGGTTTTC CC TT AAC107 558 TTTCATTGTGGAGT108 559 TTTCGAAGGAATCC109 560 TTTCTTCGGAAGC110 561 TTTGGGGCAACTCAAC Corresponding Nucleotide PositionsTo determine if a selected nucleotide position in a candidate sequence corresponds to a selected position in a reference sequence (e.g., SEQ ID NO: 622, SEQ ID NO: 623, SEQ ID NO: 624), one or more of the following Evaluations is performed.Evaluation A:! .The candidate sequence is aligned with each of the consensus sequences in Tables and 10. The consensus sequence(s) having the most positions aligned (and which has at least 60% of the positions of the candidate sequence aligned) is selected.The alignment is performed as is follows. The candidate sequence and an isodecoder consensus sequence from Tables 10A-10B are aligned based on a global pairwise alignment calculated with the Needleman-Wunsch algorithm when run with match scores from Table 11, a mismatch penalty of -1, a gap opening penalty of -1, and a gap extension penalty of -0.5, and no penalty for end gaps. The alignment with the highest overall alignment score is then used to determine the percent similarity between the candidate and the consensus sequence by counting the number of matched positions in the alignment, dividing it by the larger of the number of non- N bases in the candidate sequence or the consensus sequence, and multiplying the result by 100. In cases where multiple alignments (of the candidate and a single consensus sequence) tie for the same score, the percent similarity is the largest percent similarity calculated from the tied alignments. This process is repeated for the candidate sequence with each of the remaining 229 WO 2024/216206 PCT/US2024/024492 isodecoder consensus sequences in Tables 10A-10B, and the alignment resulting in the greatest percent similarity is selected. If this alignment has a percent similarity equal to or greater than 60%, it is considered a valid alignment and used to relate positions in the candidate sequence to those in the consensus sequence, otherwise the candidate sequence is considered to have not aligned to any of the isodecoder consensus sequences. If there is a tie at this point, all tied consensus sequences are taken forward to step 2 in the analysis.2. Using the selected consensus sequence(s) from step 1, one determines the consensus sequence position number that aligns with the selected position (e.g., a modified position) in the candidate sequence. One then assigns the position number of the aligned position in the consensus sequence to the selected position in the candidate sequence, in other words, the selected position in the candidate sequence is numbered according to the numbering of the consensus sequence. If there were tied consensus sequences from step one, and they give different position numbers in this step 2, then all such position numbers are taken forward to step 5.3. The reference sequence is aligned with the consensus sequence chosen in step 1. The alignment is performed as described in step 1.4. From the alignment in step 3, one determines the consensus sequence position number that aligns with the selected position (e.g., a modified position) in the reference sequence. One then assigns the position number of the aligned position in the consensus sequence to the selected position in the reference sequence, in other words, the selected position in the reference sequence is numbered according to the numbering of the consensus sequence. If there is a tie at this point, all tied consensus sequences are taken forward to step 5 in the analysis.. If a value for a position number determined for the reference sequence in step 2 is the same as the value for the position number determined for the candidate sequence in step 4, the positions are defined as corresponding.Evaluation B:The reference sequence (e.g., a TREM sequence described herein) and the candidate sequence are aligned with one another. The alignment is performed as follows.The reference sequence and the candidate sequence are aligned based on a global pairwise alignment calculated with the Needleman-Wunsch algorithm when run with match scores from Table 11, a mismatch penalty of -1, a gap opening penalty of -1, and a gap extension 230 WO 2024/216206 PCT/US2024/024492 penalty of -0.5, and no penalty for end gaps. The alignment with the highest overall alignment score is then used to determine the percent similarity between the candidate and reference sequence by counting the number of matched based in the alignment, dividing it by the larger of the number of non-N bases in the candidate or reference sequence, and multiplying the result by 100. In cases where multiple alignments tie for the same score, the percent similarity is the largest percent similarity calculated from the tied alignments. If this alignment has a percent similarity equal to or greater than 60%, it is considered a valid alignment and used to relate positions in the candidate sequence to those in the reference sequence, otherwise the candidate sequence is considered to have not aligned to the reference sequence.If the selected nucleotide position in the reference sequence (e.g., a modified position) is paired with a selected nucleotide position (e.g., a modified position) in the candidate sequence, the positions are defined as corresponding.Evaluation C:The candidate sequence is assigned a nucleotide position number according to the comprehensive tRNA numbering system (CtNS), also referred to as the tRNAviz method (e.g., as described in Lin et al., Nucleic Acids Research, 47:Wl, pages W542-W547, 2 July 2019), which serves as a global numbering system for tRNA molecules. The alignment is performed as follows.1. The candidate sequence is assigned a nucleotide position according to the tRNAviz method. For a novel sequence not present in the tRNAviz database, the numbering for the closest sequence in the database is obtained. For example, if a TREM differs at any given nucleotide position from a sequence in the database, the numbering for the tRNA having the wildtype sequence at said given nucleotide position is used.2. The reference sequence is assigned a nucleotide position according to the method described in 1.. If a value for a position number determined for the reference sequence in step 1 is the same as the value for the position number determined for the candidate sequence in step 2, the positions are defined as corresponding.If the selected position in the reference sequence and the candidate sequence are found to be corresponding in at least one of Evaluations A, B, and C, the positions correspond. For example, if two positions are found to be corresponding under Evaluation A, but do not 231 WO 2024/216206 PCT/US2024/024492 correspond under Evaluation B or Evaluation C, the positions are defined as corresponding. Similarly, if two positions are found to be corresponding under Evaluation B, but do not correspond under Evaluation A or Evaluation C, the positions are defined as corresponding. In addition, if two positions are found to be corresponding under Evaluation C, but do notcorrespond under Evaluation A or Evaluation B, the positions are defined as corresponding The numbering given above is used for ease of presentation and does not imply arequired sequence. If more than one Evaluation is performed, they can be performed in any order. Table 10A.Consensus sequence computationally generated for each isodecoder by aligningmembers of the isodecoder family SEQ ID NO. Amino Acid Anticodon Consensus sequence 1200 Ala AGC GGGGAATTAGCTCAAGTGGTAGAGCGCTTG CTTAGCATGCAAGAGGTAGTGGGATCGATG CCCACATTCTCCA 1201 Ala CGC GGGGATGTAGCTCAGTGGTAGAGCGCATGC TTCGCATGTATGAGGTCCCGGGTTCGATCCC CGGCATCTCCA 1202 Ala TGC GGGGGTGTAGCTCAGTGGTAGAGCGCATGC TTTGCATGTATGAGGCCCCGGGTTCGATCCC CGGCACCTCCA 1203 Arg ACG GGGCCAGTGGCGCAATGGATAACGCGTCTG ACTACGGATCAGAAGATTCCAGGTTCGACTC CTGGCTGGCTCG 1204 Arg CCG GGCCGCGTGGCCTAATGGATAAGGCGTCTG ATTCCGGATCAGAAGATTGAGGGTTCGAGTC CCTTCGTGGTCG 1205 Arg CCT GCCCCAGTGGCCTAATGGATAAGGCACTGG CCTCCTAAGCCAGGGATTGTGGGTTCGAGTC CCACCTGGGGTA 1206 Arg TCG GACCGCGTGGCCTAATGGATAAGGCGTCTG ACTTCGGATCAGAAGATTGAGGGTTCGAGTC CCTCCGTGGTCG 1207 Arg TCT GGCTCTGTGGCGCAATGGATNAGCGCATTG GACTTCTAATTCAAAGGTTGCGGGTTCGAGTCCCNCCAGAGTCG 1208 Asn GTT GTCTCTGTGGCGCAATCGGTTAGCGCGTTCG GCTGTTAACCGNAAAGGTTGGTGGTTCGAGC CCACCCAGGGACG 232 WO 2024/216206 PCT/US2024/024492 1209 Asp GTC TCCTCGTTAGTATAGTGGTGAGTATCCCCGC CTGTCACGCGGGAGACCGGGGTTCGATTCCC CGACGGGGAG 1210 Cys GCA GGGGGTATAGCTCAGNGGGTAGAGCATTTG ACTGCAGATCAAGAGGTCCCCGGTTCAAATC CGGGTGCCCCCT 1211 Gin CTG GGTTCCATGGTGTAATGGTNAGCACTCTGGA CTCTGAATCCAGCGATCCGAGTTCAAGTCTC GGTGGAACCT 1212 Gin TTG GGTCCCATGGTGTAATGGTTAGCACTCTGGA CTTTGAATCCAGCGATCCGAGTTCAAATCTC GGTGGGACCT 1213 Glu CTC TCCCTGGTGGTCTAGTGGTTAGGATTCGGCGCTCTCACCGCCGCGGCCCGGGTTCGATTCCC GGTCAGGGAA 1214 Glu TTC TCCCTGGTGGTCTAGTGGCTAGGATTCGGCGCTTTCACCGCNGCGGCCCGGGTTCGATTCCC GGTCAGGGAA 1215 Gly CCC GCATTGGTGGTTCAGTGGTAGAATTCTCGCC TCCCACGCNGGAGACCCGGGTTCGATTCCCG GCCAATGCA 1216 Gly GCC GCATTGGTGGTTCAGTGGTAGAATTCTCGCC TGCCACGCGGGAGGCCCGGGTTCGATTCCCG GCCAATGCA 1217 Gly TCC GCGTTGGTGGTATAGTGGTGAGCATAGCTGC CTTCCAAGCAGTTGACCCGGGTTCGATTCCC GGCCAACGCA 1218 lie AAT GGCCGGTTAGCTCAGTTGGTTAGAGCGTGGT GCTAATAACGCCAAGGTCGCGGGTTCGATCC CCGTACGGGCCA 1219 He TAT GCTCCAGTGGCGCAATCGGTTAGCGCGCGGT ACTTATAATGCCGAGGTTGTGAGTTCGAGCC TCACCTGGAGCA 1220 Leu AAG GGTAGCGTGGCCGAGCGGTCTAAGGCGCTG GATTAAGGCTCCAGTCTCTTCGGGGGCGTGG GTTCGAATCCCACCGCTGCCA 1221 Leu CAA GTCAGGATGGCCGAGTGGTCNTAAGGCGCC AGACTCAAGTTCTGGTCTCCGNATGGAGGCG TGGGTTCGAATCCCACTTCTGACA 1222 Leu CAG GTCAGGATGGCCGAGCGGTCTAAGGCGCTG CGTTCAGGTCGCAGTCTCCCCTGGAGGCGTG GGTTCGAATCCCACTCCTGACA 1223 Leu TAA ACCAGGATGGCCGAGTGGTTAAGGCGTTGG ACTTAAGATCCAATGGACAGATGTCCGCGTG GGTTCGAACCCCACTCCTGGTA 233 WO 2024/216206 PCT/US2024/024492 1224 Leu TAG GGTAGCGTGGCCGAGCGGTCTAAGGCGCTG GATTTAGGCTCCAGTCTCTTCGGNGGCGTGG GTTCGAATCCCACCGCTGCCA 1225 Lys CTT GCCCGGCTAGCTCAGTCGGTAGAGCATGAG ACTCTTAATCTCAGGGTCGTGGGTTCGAGCC CCACGTTGGGCGNNN 1226 Lys TTT GCCTGGATAGCTCAGTCGGTAGAGCATCAG ACTTTTAATCTGAGGGTCCAGGGTTCAAGTC CCTGTTCAGGCG 1227 Met CAT GCCCTCTTAGCGCAGTNGGCAGCGCGTCAGT CTCATAATCTGAAGGTCCTGAGTTCGAGCCT CAGAGAGGGCA 1228 Phe GAA GCCGAAATAGCTCAGTTGGGAGAGCGTTAG ACTGAAGATCNTAAAGGTCCCTGGTTCAATC CCGGGTTTCGGCA 1229 Pro AGG GGCTCGTTGGTCTAGGGGTATGATTCTCGCT TAGGATGCGAGAGGTCCCGGGTTCAAATCC CGGACGAGCCC 1230 Pro CGG GGCTCGTTGGTCTAGGGGTATGATTCTCGCT TCGGGTGCGAGAGGTCCCGGGTTCAAATCCC GGACGAGCCC 1231 Pro TGG GGCTCGTTGGTCTAGGGGTATGATTCTCGCT TTGGGTGCGAGAGGTCCCGGGTTCAAATCCC GGACGAGCCC 1232 Ser AGA GTAGTCGTGGCCGAGTGGTTAAGGCGATGG ACTAGAAATCCATTGGGGTTTCCCCGCGCAG GTTCGAATCCTGCCGACTACG 1233 Ser CGA GCTGTGATGGCCGAGTGGTTAAGGCGTTGGACTCGAAATCCAATGGGGTCTCCCCGCGCAGGTTCGAATCCTGCTCACAGCG 1234 Ser GCT GACGAGGNNTGGCCGAGTGGTTAAGGCGAT GGACTGCTAATCCATTGTGCTCTGCACGCGT GGGTTCGAATCCCATCCTCGTCG 1235 Ser TGA GTAGTCGTGGCCGAGTGGTTAAGGCGATGG ACTTGAAATCCATTGGGGTCTCCCCGCGCAG GTTCGAATCCTGCCGGCTACG 1236 Thr AGT GGCTCCGTGGCTTAGCTGGTTAAAGCGCCTG TCTAGTAAACAGGAGATCCTGGGTTCGAATC CCAGCGGGGCCT 1237 Thr CGT GGCNCTGTGGCTNAGTNGGNTAAAGCGCCGGTCTCGTAAACCNGGAGATCNTGGGTTCGA ATCCCANCNGGGCCT 1238 Thr TGT GGCTCCATAGCTCAGNGGGTTAGAGCACTG GTCTTGTAAACCAGGGGTCGCGAGTTCAAAT CTCGCTGGGGCCT 234 WO 2024/216206 PCT/US2024/024492 1239 Trp CCA GACCTCGTGGCGCAACGGTAGCGCGTCTGA CTCCAGATCAGAAGGTTGCGTGTTCAAATCA CGTCGGGGTCA 1240 Tyr GTA CCTTCGATAGCTCAGCTGGTAGAGCGGAGG ACTGTAGATCCTTAGGTCGCTGGTTCGATTC CGGCTCGAAGGA 1241 Val AAC GTTTCCGTAGTGTAGTGGTTATCACGTTCGC CTAACACGCGAAAGGTCCCCGGTTCGAAAC CGGGCGGAAACA 1242 Val CAC GTTTCCGTAGTGTAGTGGTTATCACGTTCGC CTCACACGCGAAAGGTCCCCGGTTCGAAAC CGGGCGGAAACA 1243 Val TAC GGTTCCATAGTGTAGTGGTTATCACGTCTGC TTTACACGCAGAAGGTCCTGGGTTCGAGCCC CAGTGGAACCA 1244 iMet CAT AGCAGAGTGGCGCAGCGGAAGCGTGCTGGG CCCATAACCCAGAGGTCGATGGATCGAAAC CATCCTCTGCTA Table 10B.Consensus sequence computationally generated for each isodecoder by aligningmembers o?the isodecoder family SEQ ID NO Amino Acid Anticodon Consensus sequence 1245 Ala AGC GGGGAATTAGCTCAAGTGGTAGAGCGCTTGC TTAGCATGCAAGAGGTAGTGGGATCGATGCC CACATTCTCCANNN 1246 Ala CGC GGGGATGTAGCTCAGTGGTAGAGCGCATGCT TCGCATGTATGAGGTCCCGGGTTCGATCCCC GGCATCTCCANNN 1247 Ala TGC GGGGGTGTAGCTCAGTGGTAGAGCGCATGCTTTGCATGTATGAGGCCCCGGGTTCGATCCCC GGCACCTCCANNN 1248 Arg ACG GGGCCAGTGGCGCAATGGATAACGCGTCTGA CTACGGATCAGAAGATTCCAGGTTCGACTCC TGGCTGGCTCGNNN 1249 Arg CCG GGCCGCGTGGCCTAATGGATAAGGCGTCTGA TTCCGGATCAGAAGATTGAGGGTTCGAGTCC CTTCGTGGTCGNNN 1250 Arg CCT GCCCCAGTGGCCTAATGGATAAGGCACTGGC CTCCTAAGCCAGGGATTGTGGGTTCGAGTCC CACCTGGGGTANNN 1251 Arg TCG GACCGCGTGGCCTAATGGATAAGGCGTCTGA CTTCGGATCAGAAGATTGAGGGTTCGAGTCC CTCCGTGGTCGNNN 235 WO 2024/216206 PCT/US2024/024492 1252 Arg TCT GGCTCTGTGGCGCAATGGATNAGCGCATTGGACTTCTAATTCAAAGGTTGCGGGTTCGAGTC CCNCCAGAGTCGNNN 1253 Asn GTT GTCTCTGTGGCGCAATCGGTTAGCGCGTTCG GCTGTTAACCGNAAAGGTTGGTGGTTCGAGC CCACCCAGGGACGNNN 1254 Asp GTC TCCTCGTTAGTATAGTGGTGAGTATCCCCGCC TGTCACGCGGGAGACCGGGGTTCGATTCCCC GACGGGGAGNNN 1255 Cys GCA GGGGGTATAGCTCAGNGGGTAGAGCATTTGA CTGCAGATCAAGAGGTCCCCGGTTCAAATCC GGGTGCCCCCTNNN 1256 Gin CTG GGTTCCATGGTGTAATGGTNAGCACTCTGGA CTCTGAATCCAGCGATCCGAGTTCAAGTCTC GGTGGAACCTNNN 1257 Gin TTG GGTCCCATGGTGTAATGGTTAGCACTCTGGA CTTTGAATCCAGCGATCCGAGTTCAAATCTC GGTGGGACCTNNN 1258 Glu CTC TCCCTGGTGGTCTAGTGGTTAGGATTCGGCG CTCTCACCGCCGCGGCCCGGGTTCGATTCCC GGTCAGGGAANNN 1259 Glu TTC TCCCTGGTGGTCTAGTGGCTAGGATTCGGCGCTTTCACCGCNGCGGCCCGGGTTCGATTCCC GGTCAGGGAANNN 1260 Gly CCC GCATTGGTGGTTCAGTGGTAGAATTCTCGCCT CCCACGCNGGAGACCCGGGTTCGATTCCCGG CCAATGCANNN 1261 Gly GCC GCATTGGTGGTTCAGTGGTAGAATTCTCGCCT GCCACGCGGGAGGCCCGGGTTCGATTCCCGG CCAATGCANNN 1262 Gly TCC GCGTTGGTGGTATAGTGGTGAGCATAGCTGC CTTCCAAGCAGTTGACCCGGGTTCGATTCCC GGCCAACGCANNN 1263 He AAT GGCCGGTTAGCTCAGTTGGTTAGAGCGTGGT GCTAATAACGCCAAGGTCGCGGGTTCGATCC CCGTACGGGCCANNN 1264 He TAT GCTCCAGTGGCGCAATCGGTTAGCGCGCGGTACTTATAATGCCGAGGTTGTGAGTTCGAGCC TCACCTGGAGCANNN 1265 Leu AAG GGTAGCGTGGCCGAGCGGTCTAAGGCGCTGG ATTAAGGCTCCAGTCTCTTCGGGGGCGTGGG TTCGAATCCCACCGCTGCCANNN 1266 Leu CAA GTCAGGATGGCCGAGTGGTCNTAAGGCGCCA GACTCAAGTTCTGGTCTCCGNATGGAGGCGT GGGTTCGAATCCCACTTCTGACANNN 236 WO 2024/216206 PCT/US2024/024492 1267 Leu CAG GTCAGGATGGCCGAGCGGTCTAAGGCGCTGC GTTCAGGTCGCAGTCTCCCCTGGAGGCGTGG GTTCGAATCCCACTCCTGACANNN 1268 Leu TAA ACCAGGATGGCCGAGTGGTTAAGGCGTTGGA CTTAAGATCCAATGGACAGATGTCCGCGTGG GTTCGAACCCCACTCCTGGTANNN 1269 Leu TAG GGTAGCGTGGCCGAGCGGTCTAAGGCGCTGG ATTTAGGCTCCAGTCTCTTCGGNGGCGTGGG TTCGAATCCCACCGCTGCCANNN 1270 Lys CTT GCCCGGCTAGCTCAGTCGGTAGAGCATGAGA CTCTTAATCTCAGGGTCGTGGGTTCGAGCCCC ACGTTGGGCGNNNNNN 1271 Lys TTT GCCTGGATAGCTCAGTCGGTAGAGCATCAGA CTTTTAATCTGAGGGTCCAGGGTTCAAGTCCC TGTTCAGGCGNNN 1272 Met CAT GCCCTCTTAGCGCAGTNGGCAGCGCGTCAGT CTCATAATCTGAAGGTCCTGAGTTCGAGCCT CAGAGAGGGCANNN 1273 Phe GAA GCCGAAATAGCTCAGTTGGGAGAGCGTTAGA CTGAAGATCNTAAAGGTCCCTGGTTCAATCC CGGGTTTCGGCANNN 1274 Pro AGG GGCTCGTTGGTCTAGGGGTATGATTCTCGCTT AGGATGCGAGAGGTCCCGGGTTCAAATCCCG GACGAGCCCNNN 1275 Pro CGG GGCTCGTTGGTCTAGGGGTATGATTCTCGCTT CGGGTGCGAGAGGTCCCGGGTTCAAATCCCG GACGAGCCCNNN 1276 Pro TGG GGCTCGTTGGTCTAGGGGTATGATTCTCGCTT TGGGTGCGAGAGGTCCCGGGTTCAAATCCCG GACGAGCCCNNN 1277 Ser AGA GTAGTCGTGGCCGAGTGGTTAAGGCGATGGA CTAGAAATCCATTGGGGTTTCCCCGCGCAGG TTCGAATCCTGCCGACTACGNNN 1278 Ser CGA GCTGTGATGGCCGAGTGGTTAAGGCGTTGGA CTCGAAATCCAATGGGGTCTCCCCGCGCAGG TTCGAATCCTGCTCACAGCGNNN 1279 Ser GCT GACGAGGNNTGGCCGAGTGGTTAAGGCGAT GGACTGCTAATCCATTGTGCTCTGCACGCGT GGGTTCGAATCCCATCCTCGTCGNNN 1280 Ser TGA GTAGTCGTGGCCGAGTGGTTAAGGCGATGGACTTGAAATCCATTGGGGTCTCCCCGCGCAGG TTCGAATCCTGCCGGCTACGNNN 1281 Thr AGT GGCTCCGTGGCTTAGCTGGTTAAAGCGCCTG TCTAGTAAACAGGAGATCCTGGGTTCGAATC CCAGCGGGGCCTNNN 237 WO 2024/216206 PCT/US2024/024492 1282 Thr CGT GGCNCTGTGGCTNAGTNGGNTAAAGCGCCGGTCTCGTAAACCNGGAGATCNTGGGTTCGAAT CCCANCNGGGCCTNNN 1283 Thr TGT GGCTCCATAGCTCAGNGGGTTAGAGCACTGG TCTTGTAAACCAGGGGTCGCGAGTTCAAATC TCGCTGGGGCCTNNN 1284 Trp CCA GACCTCGTGGCGCAACGGTAGCGCGTCTGAC TCCAGATCAGAAGGTTGCGTGTTCAAATCAC GTCGGGGTCANNN 1285 Tyr GTA CCTTCGATAGCTCAGCTGGTAGAGCGGAGGA CTGTAGATCCTTAGGTCGCTGGTTCGATTCCG GCTCGAAGGANNN 1286 Val AAC GTTTCCGTAGTGTAGTGGTTATCACGTTCGCC TAACACGCGAAAGGTCCCCGGTTCGAAACCG GGCGGAAACANNN 1287 Val CAC GTTTCCGTAGTGTAGTGGTTATCACGTTCGCC TCACACGCGAAAGGTCCCCGGTTCGAAACCG GGCGGAAACANNN 1288 Val TAC GGTTCCATAGTGTAGTGGTTATCACGTCTGCT TTACACGCAGAAGGTCCTGGGTTCGAGCCCC AGTGGAACCANNN 1289 iMet CAT AGCAGAGTGGCGCAGCGGAAGCGTGCTGGG CCCATAACCCAGAGGTCGATGGATCGAAACC ATCCTCTGCTANNN Table 11:Score values alignment Row Candidate nucleotide Reference nucleotide Match score A A 1T T 1U T 1C C 1G G 1A N 0T N 0C N 0G N 0N A 0N T 0N C 0N G 0N N 0 238 WO 2024/216206 PCT/US2024/024492 Premature termination codons (PTC) and ORFs comprising PTCs Mutations underlie many diseases. For example, a point mutation in the open reading frame (ORF) of a gene which creates a premature stop codon (PTC) can result in alteredexpression and/or activity of a polypeptide encoded by the gene. Table 15 provides single mutations in codons encoding amino acids which can result in a stop codon. In an embodiment, a PTC disclosed herein comprises a mutation disclosed in Table 15.In an embodiment, the codon having the first sequence or the PTC comprises a mutation disclosed in Table 15. In an embodiment, the non-mutated, e.g., wildtype, codon sequence of the codon having the first sequence or the PTC is an original codon sequence provided in Table and the amino acid corresponding to the non-mutated codon is an original AA provided in Table 15.In an embodiment, the TREM, TREM core fragment or TREM fragment recognizes a stop codon and mediates incorporation of the original AA provided in Table 15 at the position of the stop codon. In an embodiment, the TREM, TREM core fragment or TREM fragment recognizes a stop codon and mediates incorporation of an amino acid belonging to the same group as the original AA, e.g., as provided in Table 16. Other genetic abnormalities, such as insertions and/or deletions can also result in a PTC in an ORF.Table 15. Select amino acids and stop codonsOriginal AA Original codon One mutation to stop codonTRP UGG UGATYR UAU UAAUAC UAGCYS UGU UGAUGC UGAGLU GAA UAAGAG UAGLYS AAA UAAAAG UAGGLN CAA UAACAG UAGSER UCA UGAUCG UAGLEU UUA UAA OR UGAUUG UAG 239 WO 2024/216206 PCT/US2024/024492 ARG CGA UGAGLY GGA UGA Table 16: Amino acids and amino acid groupings Group Amino acid Nonpolar, aliphatic R group leucine methionine isoleucine glycine alanine valinePolar, uncharged R group serine threonine cysteine proline asparagine glutaminepositively charged r group lysine arginine histidineNegatively charged R group aspartate glutamateNonpolar, aromatic R group phenylalanine tyrosine tryptophan Disclosed herein, inter alia, are endogenous ORFs comprising a codon having a firstsequence, e.g., a mutation, e.g., a PTC. An ORF having a PTC, e.g., as described herein, can be present, or part of in any gene. As an example, the ORF can be present or be part of any gene in the human genome.In an embodiment, a PTC disclosed herein is present in a gene disclosed in any one of Tables 17, 18, or 20. Exemplary genes having ORFs comprising a PTC are provided in Table 3.Table 17: Exemplary genes with ORFs having a PTCA2ML1 ARFGEF1CACNA1GCNOTI DLG4AARSI ARFGEF2 CACNAIS COG1 DELIAARS2 ARHGAP21 CACNA2D1 COL11A2 DNA2ABCA13 ARHGEF9 CACNA2D2 COL13A1 DNMIL ABCB11 ARMC4CACNB2, NSUN6 COL4A1 DNMTIABCG5 ARV1 CAD COL4A2 DNMT3A 240 WO 2024/216206 PCT/US2024/024492 ABHD5 ARX CAMTAI COL4A4 DNMT3BACAD8 ASCC3 CARS2 COL9A1 DPHIACADL ASHIL CCDC140 COQ4 DPYD-ASIACSF3 ASPH CCDC8 COQ6 DSELACTA2 ASXE2 CCM2 COX14 DSPPACTC1, ATAD3A CD40LG CPE DUOXAIACTN2 ATP2A2 CDAN1 CPEBI-ASI DUOXA2ACVRI ATP6V1B1 CDH15 CREBBP DVL1ADAR ATP8A2 CDK11A CREED1 EARS2ADAT3 AUH CEBPA CSNK2A1 EBF3ADCY5 AUTS2 CELF5 CSNK2B EBPADIPOQ AVPR2 CELSR2 CSTA EDARADIPOQ-ASI B3GLCT CEP135 CTNND2 EFHCIADIPORI B4GAT1 CEP 164 CTSA EFNB1AFF2 BCAP31 CEP83 CTSC EFTUD2ALG11 BCL11A CETP CUE3 EIF2B5ALG14 BCL11B CFI CYLD ELANEALG6 BCORL1 CHAMP 1 CYPHAI EMCIALOXE3 BEND2 CHAT DAGI EMC 1-ASIAMERI BGN CHDI DARS2 ENO3AMH BMP4 CHD4 DCX ENTPD5AMMECRI BRD4 CHD8 DDHD2 EP300AMN BRPF1 CHRM2 DDR2 EPM2AANK2 BRSK2 CHRNB1 DEAFI ERLIN2ANK3 BUBIB CIC DENND5A EVCANKS6 BUBIB-PAK6 CECN7 DGATI EZH2ANOSI C8G CLTC DHFR FAM111AAPISI CACNA1E CNGA3 DIAPH3 FAM126AAP3B2 CACNA1F CNKSR2 DISPI FAN1FANCD2 GJB6 1SLR2 LOCI 10673972 MTRFANCE GJC2 ITGA3 LOCI 12997540 MYCBP2FASTKD2 GK ITGA8 LOCI 13788297 MYCNOSFATI GLI2 ITGB6 LOC349160 MYH7BFBN2 GNAIl JMJDIC LONP1 MYL3FBP1 GNBIL KANKI LORICRIN MYOMIFDXR GNE KANSEI LPINI MYPNFGA GNRH1 KBTBD13 LPIN2 MYTILFGD1 GNS KCNA2 LRP2 NAA15FGF10 GPAA1 KCNB1 LRRTM4 NAGAFGFRI GPDIL KCND2 MAB21L2 NARS2 241 WO 2024/216206 PCT/US2024/024492 FGFR2 GRIN2A KCNE3 MAF NAXEFIBP GTPBP3 KCNMAl MARSI NCAPH2FL ADI HACE1 KCNQ5 MARS2 NCF2FLG-ASI HADH KCTD7 MASP1 NDPFLVCR1 HADHB KIDINS220 MBOAT7 NDP-AS1FLVCR2 HDAC4 KIF21B MCM3AP NDRGI FMN2 HERCI KIF6 MCM3AP-AS1NDUFA2,TMC06FOXA2 HESXI KIT MED 13 NDUFAFIFOXCI HIBCH KLHL40 MED 17 NDUFAF5FOXC2 HNF4A KLHL41 MEGF10 NDUFAF6FOXC2-AS1 HNRNPH2 KNL1 MET NDUFAF7FOXP2 HPRTI KRAS MGAT2 NDUFSIFREMI HRG LAMBI MIBI NDUFS3FRYL HUWEI LAMB2 MICU1 NEFHFTL IARS1 LAMC3 MIR302CHG NEK8FUS IBA57 LARP7 MIR5004 NEXMIFGABRG2 IDH2 LARS1 MIR6501 NFIAGAN IFNAR1 LCT MITDI NFKB1GATA2 IFT122 LEMD3 MMP13 NHEJIGATA4 IFT80 LGI4 MMP21 NICNIGAT ADI IGF2 LIAS MNXI NIDIGDF5 ILDRI LINS1 MNXI-AS2 NKX2-1GDF5-AS1 ILK, TAF10 LIPC MPDUI NLRP1GFMI INF2 LIPTI MRPS22 NLRP3GH-LCR INS-IGF2 LOC101448202 MSL3 NOD2 GHRHR IN SRLOC106804612,HBA2 MSRB3 NONOGHSR IRAKI BP I LOC107303338 MT-ND2 NOTCH3GJAl IRAK3 RARS2 SEED IB SPTLC1NPHP4 PLEKHG5 RAX SETD2 SRD5A3NPR2 PLEKHM2 RBM10 SETX SRPX2NR2F2 PLK4 RELN SFTA3 SSBP2NR5A1 PEPBP RERE SHANK2 ST3GAL3NRL, PCK2 PNKD RFT1 SHH ST3GAL5NRXNI PNPLA1 RMND1 SIN3A STAMBPNT5DC1 POCIA RNASEH1 SIX3 STAT3NTRK2 POLG2, MILRI RNF17 SKI STILNUBPL POMGNT2 ROR2 SLC13A5 STX11NUSI PPM ID RP2 SLC16A1 STXIBOCRL PPP3CA RPL11 SLC16A2 SUCLA2 242 WO 2024/216206 PCT/US2024/024492 OPEN PRDM1 RPS19 SLC17A8 SYNIP4HA1 PRDM12 RRM2B SLC18A3 SYN2PAK6 PREPL RSI SLC20A2 SYNJIPBXI PRICKLEI RUNX2 SLC25A4 TAB2PCARE PRKAG2 RXYLT1 SLC25A46 TACR3PCDH12 PRO SI S100PBP SLC2A1 TBCDPDCD10 PRPF31 SALL4 SLC39A8 TBLIXRIPDE11A-AS1 PRPF8 SAMD9 SLC52A2 TBXIPDE4D PRPSI SARIB SLC6A3 TBX18PDE6A PRSSI, TRB SASH3 SLC6A8 TCIRG1PDHX PSATI SBF2 SLC6A9 TELO2PDLIM3 PSMD12 SBF2-AS1 SLC7A9 TFAP2APDP1 PSTPIP1 SCAMP4 SMAD2 TFGPDSS1 PTCHDI SCLTI SMAD9 TGIF1PEX5 PTF1A SCN10A SMARCA2 THAPIPHF21A PTPN23 SCN11A SMC3 TINF2PHF8 PTPRQ SCNIB SMOC2 TLK2PHKA2 PTRH2 SCN3A SNTA1 TMEM43PHKB PUS1 SCN4A SNX14 TMIEPIEZO 1 PYCR2 SCN4B SNX22 TMPOPIGG QARSI SCN8A SOCSI TMPRSS15 PIGLRAB3GAP1,ZRANB3 SCO2 SOX11 TMTC3PIGM RAB3GAP2 SCYLI SOX17 TNFAIP3PIGP RAC1 SEMA4A SPATA5 TNFRSF11APIK3CA RAFI SEPTIN9 SPATA7 TOEIPIN4, ERCC6L RAGI SET SPREDI TORIAIP1PLATRARE SETD1A SPTBN2 TPK1TPM1 UTP14C ZEBITRAPPC9 VPS53 ZFHX4TRIM37 WDR19 ZFPM2TRIM59-IFT80 WDR26 ZFPM2-AS1TRIO WDR62 ZIC1TRIP 12 WDR81 ZIC2TRIP4 WNTI ZMYND11TRPM1 WNT10A ZNF335TSEN54 WRAPS 3 ZNF423TUBA4A WWOX ZNF469TUBGCP4 YARSITUBGCP6 YARS2 243 WO 2024/216206 PCT/US2024/024492 TWNK YYlTXNRD2 ZAP70UBA2 ZBTB20UBA5 ZBTB24UMOD ZC4H2UNC5B ZDHHC9 Additional exemplary genes containing a PTC include FVIII, FIX, CFTR, MeCP2, NAGLU, DMD, GAA, RP1, RP2, ABCA4, PCDH15, REP1, GLA, MUT, TP53, and ATM. In an embodiment, the PTC is present within the FVIII gene and comprises an R mutation, e.g., an R2228X mutation. In an embodiment, the PTC is present within the FIX gene and comprises an R mutation, e.g., an R29X mutation, an RI 16X mutation, an R248X mutation, an R252X mutation, an R333X mutation, and/or an R338X mutation. In an embodiment, the PTC is present within the CFTR gene and comprises an R mutation, e.g., an R553X mutation. In an embodiment, the PTC is present within the MeCP2 gene and comprises an R mutation, e.g., an R168X mutation. In an embodiment, the PTC is present within the NAGLU gene and comprises an R mutation, e.g., an R626X mutation. In an embodiment, t the PTC is present within the DMD gene and comprises an R mutation, e.g., an R3881X mutation. In an embodiment, the PTC is present within the GAA gene and comprises an R mutation, e.g., an R854X mutation. In an embodiment, the PTC is present within the RP1 gene and comprises an R mutation, e.g., an R667X mutation. In an embodiment, the PTC is present within the RP2 gene and comprises an R mutation, e.g., an R120X mutation. In an embodiment, the PTC is present within the ABCAgene and comprises an R mutation, e.g., an R2030X mutation. In an embodiment, the PTC is present within the PCD gene and comprises an R mutation, e.g., an R245X mutation. In an embodiment, the PTC is present within the REP1 gene and comprises an R mutation, e.g., an R270X mutation. In an embodiment, the PTC is a mutation in the GLA gene, e.g., an R220X mutation and/or an R227X mutation. In an embodiment, the PTC is present within the MUT gene and comprises an R mutation, e.g., an R228X mutation, an R403X mutation, an R467X mutation, and/or an R727X mutation. In an embodiment, the PTC is present within the TPgene and comprises an R mutation, e.g., an R578X mutation. In an embodiment the PTC is present within the ATM gene and comprises an R mutation, e.g., an R35X mutation. 244 WO 2024/216206 PCT/US2024/024492 Diseases or disorders associated with a PTC A TREM composition disclosed herein can be used treat a disorder or disease associated with a PTC, e.g., as described herein. Exemplary diseases or disorders associated with a PTC are listed in Tables 18, 19, and 20.In an embodiment, the subject has a disease or disorder provided in any one of Tables 4- 6. In an embodiment, the cell is associated with, e.g., is obtained from a subject who has, a disorder or disease listed in any one of Tables 18-20.For example, the disorder or disease can be chosen from the left column of Table 18. As another example, the disorder or disease is chosen from the left column of Table 18 and, in embodiments the PTC is in a gene chosen from the right column of Table 18, e.g., any one of the genes provided in the right column of Table 18. In some embodiments, the PTC is in a gene corresponding to the disorder or disease provided in the left column of Table 18. As a further non-limiting example, the PTC can be at a position provided in Table 18.As another example, the disorder or symptom is chosen from a disorder or disease provided in Table 19.As yet another exmaple, the disorder or symptom is chosen from a disorder or disease provided in Table 20. In an embodiment, the disorder or symptom is chosen from a disorder or disease provided in Table 20 and, in embodiments, the PTC is in any gene provided in Table 20. In an embodiment, the disorder or symptom is chosen from a disorder or disease provided in Table 20 and the PTC is in a corresponding gene provided in Table 20, e.g., a gene corresponding to the disease or disorder. In an embodiment, the disorder or symptom is chosen from a disorder or disease provided in Table 20 and the PTC is not in a gene provided in Table 20.In an embodiment of any of the methods disclosed herein, the PTC is at any position within the ORF of the gene, e.g., upstream of the naturally occurring stop codon.Table 18: Exemplary diseases or disorders Disease/disorder or protein Exemplary Point Mutation G to A point mutations Dihydropyrimidine dehydrogenase deficiencyNM 000110.3(DPYD):c.l905+lG>A Noonan syndrome NM 005633.3(SOSl):c.2536G>A (p.Glu846Lys) 245 WO 2024/216206 PCT/US2024/024492 Lynch syndrome NM 000251.2(MSH2):c.212-lG>ABreast-ovarian cancer, familial 1 NM 007294.3(BRCAl):c.963G>A (p.Trp321Ter)Cystic fibrosis NM 000492.3(CFTR):c.57G>A (p.Trpl9Ter)Anemia, due to G6PD deficiency NM 000402.4(G6PD):c.292G>A (p.Val98Met)AVPR2Nephrogenic diabetes insipidus, X-linkedNM 000054.4(AVPR2):c.878G>A (p.Trp293Ter)FANCCFanconi anemia, complementation group CNM 000054.4(AVPR2):c.878G> A (p.Trp293Ter)FANCCFanconi anemia, complementation group CNM 000136.2(FANCC):c. 1517G>A (p.Trp506Ter)IL2RGX-linked severe combined immunodeficiency NM 000206.2(IL2RG):c.710G>A (p.Trp237Ter) F8 Hereditary factor VIII deficiency diseaseNM 000132.3(F8):c.3144G> A (p.TrplO48Ter)LDLRFamilial hypercholesterolemiaNM 000527.4(LDLR):c. 1449G>A (p.Trp483Ter)CBSHomocystinuria due to CBS deficiencyNM 000071.2(CBS):c.l62G> A(p.Trp54Ter)HBBbetaThalassemiaNM 000518.4(HBB):c. 114G>A (p.Trp38Ter)ALDOBHereditary fmctosuriaNM 000035.3(ALDOB):c.888G>A (p.Trp296Ter)DMDDuchenne muscular dystrophyNM 004006.2(DMD):c.3747G> A (p.Trpl249Ter)SMAD4Juvenile polyposis syndromeNM 005359.5(SMAD4):c.906G>A (p.Trp302Ter)BRCA2Familial cancer ofbreastlBreast-ovarian cancer, familial 2NM 000059.3(BRCA2):c.582G>A (p.Trpl94Ter)GRIN2AEpilepsy, focal, with speech disorder and with or without mental retardationNM 000833.4(GRIN2A);c.3813G>A (p.Trpl271Ter)SCN9AIndifference to pain, congenital, autosomal recessiveNM 002977.3(SCN9A):c.2691G>A (p.Trp897Ter)TARDBPAmyotrophic lateral sclerosis type 10NM 007375.3(TARDBP):c.943G>A (p.Ala315Thr)CFTRCystic fibrosislHereditary pancreati ti si not provi dedi atal uren response - Efficacy NM 000492.3(CFTR):c.3846G>A (p.Trpl282Ter) UBE3A NM 130838. l(UBE3A):c.2304G>A 246 WO 2024/216206 PCT/US2024/024492 Angelman syndrome (p.Trp768Ter)SMPD1Niemann-Pick disease, type ANM 000543.4(SMPDl):c.l68G> A (p.Trp56Ter)USH2AUsher syndrome, type 2ANM 206933.2(USH2A):c.9390G>A (p.Trp3130Ter)MENIHereditary cancer-predisposing syndromeNM 130799.2(MENl):c.l269G>A (p.Trp423Ter)C8orf37Retinitis pigmentosa 64NM 177965.3(C8orf37):c.555G> A (p.Trpl85Ter)MLH1Lynch syndromeNM 000249.3(MLHl):c. 1998G> A (p.Trp666Ter)TSC2Tuberous sclerosis 21 Tuberous sclerosis syndrome 46NM 000548.4(TSC2):c.2108G>A (p.Trp703Ter)NF1Neurofibromatosis, type 1NM 000267.3(NFl):c.7044G>A (p.Trp2348Ter)MSH6Lynch syndromeNM 000179.2(MSH6):c.3020G>A (p.Trpl007Ter)SMN1Spinal muscular atrophy, type III Kugelberg- Welander diseaseNM 000344.3(SMNl):c.305G> A (p.TrplO2Ter)SH3TC2Charcot-Marie-Tooth disease, type 4CNM 024577.3(SH3TC2):c.920G>A(p.Trp307Ter)DNAH5Primary ciliary dyskinesiaNM 001369.2(DNAH5):c.8465G> A (p.Trp2822Ter)MECP2Rett syndromeNM 004992.3(MECP2):c.311G>A (p.TrplO4Ter)ADGRV1Usher syndrome, type 2CNM 032119.3(ADGRVl):c.7406G>A (p.Trp2469Ter)AHilJoubert syndrome 3NM 017651.4(AHIl):c.2174G>A (p.Trp725Ter)PRKNParkinson disease 2NM 004562.2(PRKN):c.l358G>A (p.Trp453Ter)COL3A1Ehlers-Danlos syndrome, type 4NM 000090.3(COL3Al):c.3833G>A (p.Trpl278Ter)BRCA1Familial cancer ofbreastlBreast-ovarian cancer, familial 1 NM 007294.3(BRCAl):c.5511G>A (p.Trpl837Ter) MYBPC3Primary familial hypertrophic cardiomyopathy NM 000256.3(MYBPC3):c.3293G>A (p.Trpl098Ter) APCFamilial adenomatous polyposis 1NM 000038.5(APC):c.l262G>A (p.Trp421Ter)BMPR2Primary pulmonary hypertensionNM 001204.6(BMPR2):c.893G>A(p.W298*) 247 WO 2024/216206 PCT/US2024/024492 T to C point mutations Wilson disease NM_000053.3(ATP7B):c.3443T>C (pile 1148Thr)Leukodystrophy, hypomyelinating, 2 NM_02043 5.3 (GJC2): c. 85 7T>C(p.Met286Thr)Alport syndrome, X-linked recessive NM_000495.4(COL4A5):c.438+2T>CLeigh disease NC 012920.1:m.9478T>CGaucher disease, type 1 NM_001005741.2(GBA):c.751T>C (p.Tyr251His)Renal dysplasia, retinal pigmentary dystrophy, cerebellar ataxia and skeletal dysplasia NM_014714.3(IFT140):c.4078T>C (p.Cysl360Arg) Marfan syndrome NM_00013 8.4(FBN1): c. 3 793 T>C (p.Cysl265Arg)Deficiency of UDPglucose-h exose- 1 - phosphate uridylyltransferaseNM_000155.3 (GALT): c. 482T>C (p.Leul61Pro)Familial hypercholesterolemia NM_000527.4(LDLR):c.694+2T>CEpisodic pain syndrome, familial, 3 NM_001287223.1(SCN11 A):c. 1142T>C(p.He381Thr)Navajo neurohepatopathy NM_00243 4 . ר(MP V17): c. 186+2T>CCongenital muscular dystrophy, LMNA- relatedNM_1 70707.3(LMNA):c.H39T>C (p.Leu380Ser)Hereditary factor VIII deficiency disease NM_000132.3(F8):c.5372T>C (p.Metl 791Thr)Insulin-dependent diabetes mellitus secretory diarrhea syndromeNM_014009.3(FOXP3):c.970T>C(p.Phe324Leu)Hereditary factor IX deficiency disease NM_000133.3(F9):c.l328T>C (p.Ile443Thr)Familial cancer of breast, Breast-ovarian cancer, familial 2, Hereditary cancer predisposing syndrome NM_00005 9.3 (BRC A2): c. 316+2T>C Cardiac arrhythmia NM_000238.3(KCNH2):c. 1945+6T>CTangier disease NM_005502.3(ABCAl):c.4429T>C(p.Cysl477Arg)Dilated cardiomyopathy 1AA NM_001103.3(ACTN2):c.683T>C (p.Met228Thr)Mental retardation 3, X-linked NM 005334.2(HCFCl):c.-970T>CLimb-girdle muscular dystrophy, type 2B NM_003494.3(DYSF):c. 1284+2T>CMacular dystrophy, vitelliform, 5 NM 016247.3 (IMPG2): c. 3 70T>C (p.Phel24Leu)Retinitis pigmentosa NM_000322.4(PRPH2):c.736T>C (p.Trp246Arg) 248 WO 2024/216206 PCT/US2024/024492 Table 19: Additional exemplary disorders5q-syndrome Holt-Oram syndromeAdams-Oliver syndrome- 1 HypoparathyroidismAdams-Oliver syndrome-3 Intellectual disabilityAdams-Oliver syndrome-5 Kleefstra syndrome 1Adams-Oliver syndrome-6 Klippel-Trenaunay syndrome (AAGF-related)Alagille syndrome- 1 Marfan syndromeAutoimmune lymphoproliferative syndrome type IAMental retardationAutoimmune lymphoproliferative syndrome type VMental retardationAutosomal dominant deafness-2A Mental retardationBrain malformations with or without urinary tract defects (BRMUTD)Mental retardation and distinctive facial features with or without cardiac defects (MRFACD)Carney complex type 1 Nail-patella syndrome (NPS)CHARGE syndrome ObesityCleidocranial dysplasia Phelan-McDermid syndromeCurrarino syndrome Pitt-Hopkins syndromeDenys-Drash syndrome / Frasier syndrome Primary pulmonary hypertension- 1Developmental delay Rett syndrome (congenital variant)Di George syndrome (TB XI-associated) Sensorineural deafnessDravet syndrome Smith-Magenis syndrome (RAH-associated)Duane-radial ray syndrome Sotos syndrome- 1Ehlers-Danlos syndrome (classic-like) Sotos syndrome-2Ehlers-Danlos syndrome (vascular type) Stickler syndrome type 1Feingold syndrome- 1 Supravalvular aortic stenosisFeri-Weill dyschondrosteosis SYNGAPI-related intellectual disabilityFrontotemporal lobar degeneration with TDP43 inclusions (FTFD-TDP)Treacher Collins syndromeGFUT1 deficiency syndrome Trichorhinophalangeal syndrome type 1Greig cephalopolysyndactyly syndrome Ulnar-mammary syndromeHereditary hemorrhagic telangiectasia type 1 van der Woude syndrome- 1Holoprosencephaly-3 Waardenburg syndrome type 1Holoprosencephaly-4 Waardenburg syndrome type 2AHoloprosencephaly-5 Waardenburg syndrome type 4C Table 20: Exemplary genes with ORFs comprising a PTC and exemplary disorders Gene Disease/Disorder AAAS Glucocorticoid deficiency with achalasiaAAGAB Keratosis palmoplantaris papulosaAASS Hyperlysinemia 249 WO 2024/216206 PCT/US2024/024492 ABCAl Tangier diseaseABCA12, SNHG31 Autosomal recessive congenital ichthyosis-4BABCA3 Surfactant metabolism dysfunction-3 ABCA4 Bietti crystalline corneoretinal dystrophy; Cone-rod degeneration; Cone-rod dystrophy-3; Macular dystrophy; Retinal dystrophy; Retinitis pigmentosa;Retinitis pigmentosa- 19; Stargardt disease; Stargardt disease type 1 ABCB4Intrahepatic cholestasis of pregnancy -3; Progressive familial intrahepatic cholestasis-3ABCC2 Dubin-Johnson syndrome ABCC6Cutis laxa; Generalized arterial calcification of infancy-2; Papule; Pseudoxanthoma elasticum forme frusteABCC8 Familial hyperinsulinism;Familial hyperinsulinemic hypoglycemia- 1 ABCC9 Arrhythmogenic right ventricular cardiomyopathy; Cardiomyopathy;Cardiovascular phenotype; Dilated cardiomyopathy-10; Primary dilated cardiomyopathyABCDI Adrenoleukodystrophy; Spastic gait; Spastic paraplegiaABHD12 Polyneuropathy; Cataract; Ataxia; Hearing loss; Retinitis pigmentosaABRAXAS 1 Hereditary breast and ovarian cancer syndromeACAD9 Deficiency of acyl-CoA dehydrogenase family member 9ACADM Medium-chain acyl-coenzyme A dehydrogenase deficiencyACADS Deficiency of butyryl-CoA dehydrogenaseACADVL Very long chain acyl-CoA dehydrogenase deficiencyACAN Osteochondritis dissecans; Kimberly type spondyloepiphyseal dysplasiaACATI Deficiency of acetyl-CoA acetyltransferaseACBD5 Retinal dystrophy with leukodystrophyACBD6, LHX4, LHX4-AS1 Short stature; Pituitary and cerebellar defects; Small sella turcica syndromeACE Renal dysplasiaACOXI Peroxisomal acyl-CoA oxidase deficiencyACP5 Spondyloenchondrodysplasia with immune dysregulationACP5, ZNF627 Spondyloenchondrodysplasia with immune dysregulationACTAl Congenital myopathy with excess of thin filamentsACTB Baraitser-Winter syndrome ACVRL1 Hereditary hemorrhagic telangiectasia type 1; Primary pulmonary hypertension; Pulmonary arterial hypertension related to hereditary hemorrhagic telangiectasia; ; Hereditary hemorrhagic; Telangiectasia type 2ACYl Neurological conditions associated with aminoacylase-1 deficiency ADASevere combined immunodeficiency disease; Severe combined immunodeficiency due to ADA deficiencyADAM10 Reticulate acropigmentation of KitamuraADAMTS17 Weill-Marchesani syndrome type 4ADAMTS2 Dermatosparaxis-type Ehlers-Danlos syndrome 250 WO 2024/216206 PCT/US2024/024492 ADAMTSL4Ectopia lentis; Ectopia lentis et pupillae; Isolated autosomal recessive ectopia lentis-2ADCY3 Body mass index quantitative trait locus- 19ADCY3, CENPO Body mass index quantitative trait locus- 19ADGRG1 Bilateral frontoparietal polymicrogyria ADGRG2Congenital bilateral aplasia of vas deferens from CFTR mutation; X-linked congenital bilateral aplasia of vas deferens ADGRG6Arthrogryposis multiplex congenita; Lethal congenital contracture syndrome-9 ADGRV1Familial febrile seizures-4; Rare genetic deafness; Retinal dystrophy; Usher syndrome type 2C ADNPHelsmoortel-Van der Aa Syndrome; History of neurodevelopmental disorder; Inborn genetic diseasesAEBP1 Classic-like Ehlers-Danlos syndrome-2AGA AspartylglucosaminuriaAGK Sengers syndromeAGK, DENND11 Congenital autosomal recessive cataract-5; Sengers syndrome AGLGlycogen storage disease; Glycogen storage disease type Illa; Glycogen storage disease type 111b; Glycogen storage disease type IIIAGPAT2 Congenital generalized lipodystrophy type 1AGRN Congenital myasthenic syndromeAGT Renal dysplasiaAGTR1 Renal dysplasiaAGXT Primary hyperoxaluria type 1 AHDC1 Delayed speech and language development; Global developmental delay; Intellectual disability; Muscular hypotonia; Neonatal hypotonia; Sleep apnea; Xia-Gibbs syndrome AH 11Joubert syndrome; Joubert syndrome-3; Retinal dystrophy; Retinitis pigmentosaAHR Retinitis pigmentosa-85 AIREAutoimmune polyglandular syndrome type 1; Autoimmune polyglandular syndrome type 1 with reversible metaphyseal dysplasiaALB AnalbuminemiaALDH18A1 Cutis laxa; Corneal clouding; Oligophrenia syndromeALDH3A2 Sjogren-Larsson syndromeALDH5A1 Succinate-semialdehyde dehydrogenase deficiencyALDH7A1 Pyridoxine-dependent epilepsy; SeizuresALDOB Hereditary fructosuriaALG1 Congenital disorder of glycosylationALG3 Congenital disorder of glycosylationALMSI Al strom syndrome 251 WO 2024/216206 PCT/US2024/024492 ALOX12B Autosomal recessive congenital ichthyosis-2ALPK3 Familial hypertrophic cardiomyopathy-27; Hypertrophic cardiomyopathyALPL Hypophosphatasia; Infantile hypophosphatasia ALS2Amyotrophic lateral sclerosis type 2; Infantile-onset ascending hereditary spastic paralysis; Juvenile primary lateral sclerosisALX4 Parietal foramina-2AMPD2 Pontocerebellar hypoplasia type 9AMT Non-ketotic hyperglycinemiaANAPCI Rothmund-Thomson syndrome type 1ANGPTL3, DOCK? Familial h;ypobetalipoproteinemia-2 ANKRD1ANKRD1-related dilated cardiomyopathy; Cardiovascular phenotype; Primary dilated cardiomyopathy ANKRDU Abnormal facial shape; Clinodactyly of the 5th finger; Conductive hearing impairment; Delayed speech and language development; Global developmental delay; Inborn genetic diseases; Intellectual disability; KBG syndrome; Ptosis; Seizures; Short foot; Short palm; Unilateral cryptorchidism ANO 10Autosomal recessive cerebellar ataxia; Autosomal recessive spinocerebellar ataxia- 10 ANO5 ANO5-related disorders; Achilles tendon contracture; Elevated serum creatine phosphokinase; Gnathodiaphyseal dysplasia; Limb-girdle muscular dystrophy; Lower limb amyotrophy; Lower limb muscle weakness; Miyoshi muscular dystrophy-3; Muscular diseases; Polycystic kidney dysplasia type 2LANTXRI Odontotrichomelic syndromeAP1B1 Autosomal recessive keratitis-ichthyosis-deafness syndromeAP3B1 Hermansky-Pudlak syndrome type 2AP4B1, AP4B1- ASI Inborn genetic diseases; Autosomal recessive spastic paraplegia-47AP4M1 Autosomal recessive spastic paraplegia-50AP5Z1 Autosomal recessive spastic paraplegia-48 APC Adenomatous colonic polyposis; Adenomatous polyposis coli with congenital cholesteatoma; Brain tumor-polyposis syndrome-2; Carcinoma of colon; Colon adenocarcinoma; Colorectal cancer; Craniopharyngioma; Desmoid disease; Desmoid tumors; Duodenal polyposis; Familial adenomatous polyposis; Familial adenomatous polyposis-1; Familial multiple polyposis syndrome; Gardner syndrome; Gastric polyposis; Hepatocellular carcinoma; Hereditary cancer-predisposing syndrome; Hyperplastic colonic polyposis; Intestinal polyp; Malignant colorectal neoplasm; Neoplasm of stomach; Neoplasm of the large intestine;Periampullary adenomaAPOAl, APOAl-AS Familial hypoalphalipoproteinemia 252 WO 2024/216206 PCT/US2024/024492 APOBFamilial hypobetalipoproteinemia-1; Normotriglyceridemic familial hypobetalipoproteinemiaAPOC2 Nijmegen apolipoprotein C-II deficiency; Apolipoprotein C2 deficiencyAPOC2,APOC4-APOC2 Padova apolipoprotein C-II deficiency; Apolipoprotein C2 deficiencyAPTX Ataxia-oculomotor apraxia type 1 ARAndrogen resistance syndrome; X-linked bulbo-spinal atrophy; Partial androgen insensitivity syndrome ARCNIRhizolemic short stature, micrognathia, and developmental delay with microcephalyARGI, MED23 Arginase deficiencyARHGEF18 Retinitis pigmentosa-78ARIDIA Autosomal dominant mental retardation- 14 ARIDIB Absent speech; Blepharophimosis; Coffin-Siris syndrome-1; Constipation;Decreased body weight; Failure to thrive; Inborn genetic diseases;Intellectual disability; Long eyelashes; Microcephaly; Recurrent respiratory infections; Seizures; Short stature; Thick lower lip vermilion; Thin upper lip vermilionARID2 Coffin-Siris syndrome type 6ARL2BP Retinitis pigmentosa-82 with or without situs inversus ARMC2Male infertility with teratozoospermia due to single gene mutation; Spermatogenic failure-38; Sperm tail anomalyARMC2, ARMC2-AS1Male infertility with teratozoospermia due to single gene mutation; Spermatogenic failure-38ARMC5 Acth-independent macronodular adrenal hyperplasia-2 ARSALate infantile metachromatic leukodystrophy; Pseudoaryl sulfatase A deficiencyARSB Metachromatic leukodystrophy; Mucopolysaccharidosis type 6ART4 Dombrock blood group system ASAHIFarber disease; Spinal muscular atrophy-progressive myoclonic epilepsy syndromeASL Argininosuccinate lyase deficiencyASP A, SPATA22 Canavan disease; Familial spongy degeneration of central nervous system ASPM Microcephaly; Primary autosomal recessive microcephaly; Primary autosomal recessive microcephaly-1; Primary autosomal recessive microcephaly -5ASSI Citrullinemia type 1ASXEl Bohring-Opitz syndrome; Inborn genetic diseasesASXE3 Bainbridge-Ropers syndromeATF6 Achromatopsia; Achromatopsia- 7ATL1 Hereditary spastic paraplegia-3 A 253 WO 2024/216206 PCT/US2024/024492 ATM Ataxia-telangiectasia syndrome; Familial cancer of breast; Hereditary breast and ovarian cancer syndrome; Hereditary cancer-predisposing syndrome; Ovarian neoplasms ATM, C110rf65, ATP13A2 Ataxia-telangiectasia syndrome; Ataxia-telangiectasia without immunodeficiency; Breast cancer; Familial cancer of breast; Hereditary breast and ovarian cancer syndrome; Hereditary cancer-predisposing syndrome; Neoplasm of the breast; Susceptibility to Kufor-Rakeb syndrome ATP1A2Abnormality of neuronal migration; Arthrogryposis multiplex congenita; Epilepsy; Hydrops fetalisATP2A1 Brody myopathyATP2C1 Familial benign pemphigusATP6VOA2 ALG9 congenital disorder of glycosylation; Cutis laxa with osteodystrophyATP6VOA4 Autosomal recessive distal renal tubular acidosisATP7A Cutis laxa; X-linked Menkes kinky-hair syndromeATP7B Inborn genetic diseases; Wilson disease ATRX Alpha thalassemia-X-linked intellectual disability syndrome; Intellectual disability; Mental retardation-hypotonic facies syndrome; X-linked mental retardation-hypotonic facies syndrome- 1AXIN2 Oligodontia-colorectal cancer syndromeB3GALNT1 P-blood group phenotype B3GALNT2Congenital muscular dystrophy-dystroglycanopathy type A-l 1 with brain and eye anomaliesB3GALT6 Spondylo-epi-metaphyseal dysplasiaB4GALNT1 Hereditary spastic paraplegia-26; Inborn genetic diseasesB4GALT7 Progeroid type Ehlers-Danlos syndromeB9D1 Joubert syndrome; Meckel syndrome; Meckel-Gruber syndrome type 9B9D2 Joubert syndrome BAG3 BAG3-related cardiovascular phenotype; Dilated cardiomyopathy-1HH; Inborn genetic diseases; Myofibrillar myopathy; Primary dilated cardiomyopathy BAP1Hereditary cancer-predisposing syndrome; Tumor susceptibility linked to germline BAP1 mutations BARDI Breast cancer; Familial cancer of breast; Hereditary breast and ovarian cancer syndrome; Hereditary cancer-predisposing syndrome; Triple- negative breast cancerBBSI Bardet-Biedl syndromeBBSI,ZDHHC24 Bardet-Biedl syndrome; Bardet-Biedl syndrome- 1 BBS10 Bardet-Biedl syndrome; Bardet-Biedl syndrome-1; Bardet-Biedl syndrome- 10; Digenic Bardet-biedl syndrome-6/10; Inborn genetic diseases; Retinal dystrophy; Retinitis pigmentosa BBS2 Bardet-Biedl syndrome; Bardet-Biedl syndrome-2; Digenic Bardet-Biedl syndrome-1/2; Digenic Bardet-biedl syndrome-2/6; Retinal dystrophy;Retinitis pigmentosa; Retinitis pigmentosa-74 254 WO 2024/216206 PCT/US2024/024492 BBSS Bardet-Biedl syndrome- 5BBS9 Bardet-Biedl syndromeBCKDHA Maple syrup urine disease; Maple syrup urine disease type-lA BCKDHBClassic; maple syrup urine disease type IB; Maple syrup urine disease; Maple syrup urine disease type IBBCOR Oculofaciocardiodental syndrome BCSIL BCSIL-related disorders; Gracile syndrome; Leigh syndrome;Mitochondrial complex III deficiency nuclear type 1; Pili torti-deafness syndrome BESTIAutosomal recessive bestrophinopathy; Retinal dystrophy; Vitelliform macular dystrophy type 2BET1 Progressive muscle weakness; SeizuresBFSP1 Cataract-33 (multiple types) BEMBloom syndrome; Hereditary breast and ovarian cancer syndrome; Hereditary cancer-predisposing syndromeBMP1 Osteogenesis imperfecta type XIII BMP2Skeletal anomalies with or without cardiac anomalies; Facial dysmorphism; Short statureBMPRIA Hereditary cancer-predisposing syndrome; luvenile polyposis syndromeBMPR2 Primary pulmonary hypertensionBNC1 Premature ovarian failure- 16BOLA3 Multiple mitochondrial dysfunctions syndrome-2BPNT2 GPAPP type chondrodysplasia with joint dislocations BPTFNeurodevelopmental disorder with dysmorphic facies and distal limb anomalies BRATI inborn genetic diseases; Neurodevelopmental disorder with cerebellar atrophy and with or without seizures; Lethal neonatal rigidity and multifocal seizure syndrome BRCA1 Breast and/or ovarian cancer; Breast carcinoma; Familial breast-ovarian cancer-1; Dysgerminoma; Complementation group S Fanconi anemia; Familial cancer of breast; Hereditary breast and ovarian cancer syndrome; Hereditary cancer-predisposing syndrome; infiltrating duct carcinoma of breast; Neoplasm of ovary; Neoplasm of the breast; Ovarian neoplasms; Ovarian serous surface papillary adenocarcinoma; Ovarian cancer; Pancreatic cancer; Pancreatic cancer-4; Porokeratosis punctata palmaris et plantaris; Rhabdomyosarcoma; Bilateral breast cancer; Breast cancer BRCA2 Asthma; BRCA2-related disorders; Breast and/or ovarian cancer; Breast carcinoma; Breast-ovarian cancer; Cancer of the pancreas; Colorectal cancer; Diffuse intrinsic pontine glioma; Ectopic ossification; Familial cancer of breast; Complementation group Di Fanconi anemia; Focal seizures; Genetic non-acquired premature ovarian failure; Glioma susceptibility-3; Headache; Hereditary cancer syndrome; Hereditary breast and ovarian cancer syndrome; Hereditary cancer-predisposing syndrome; Inborn genetic diseases; Malignant tumor of prostate; Medulloblastoma; 255 WO 2024/216206 PCT/US2024/024492 Migraine; Muscle weakness; Neoplasm of the breast; Nephrolithiasis; Obesity; Ovarian neoplasms; Ovarian cancer; Pancreatic cancer-2; Polydactyly; Short attention span; Striae distensae; Tracheoesophageal fistula; Tumor susceptibility linked to germline BAP1 mutations; Wilms tumor- 1 BRIPI BRIP1-related disorders; Breast cancer; Carcinoma of colon; Familial cancer of breast; Complementation group J Fanconi anemia; Hereditary breast and ovarian cancer syndrome; Hereditary cancer-predisposing syndrome; Neoplasm of ovary; Neoplasm of the breast; Ovarian Cancers; Ovarian Neoplasms; Tracheoesophageal fistulaBRWD3 X-linked mental retardation-93BSND Bartter disease type 4ABID Biotinidase deficiency BTKNon-Bruton agammaglobulinemia; X-linked agammaglobulinemia; X- linked agammaglobulinemia with growth hormone deficiency C110rf65, ATMAtaxia-telangiectasia syndrome; Hereditary breast and ovarian cancer syndrome; Hereditary cancer-predisposing syndrome C12orf4Autosomal recessive mental retardation-66; Attention deficit hyperactivity disorder; Intellectual disability; Muscular hypotoniaC120rf65 Combined oxidative phosphorylation deficiency-7; Spastic paraplegia C190rfl2Neurodegeneration with brain iron accumulation-4; Autosomal recessive spastic paraplegia-43C1QB Clq deficiencyCIS Complement component Cis deficiencyC2 Complement component 2 deficiencyC2CD3 Orofaciodigital syndrome-XIVC5 Leiner disease C6Complement component 6 deficiency; Immunodeficiency due to a late component of complement deficiencyC7 Complement component 7 deficiency C8BComplement component 6 deficiency; Type II complement component deficiencyC8orG7 Cone-rod dystrophy- 16C8orC7 Retinitis pigmentosa-64CA2 Osteopetrosis with renal tubular acidosisCABP4 Congenital stationary night blindness type 2B CACNA1ABulbar palsy; early infantile epileptic encephalopathy -42; Episodic ataxia;Episodic ataxia type 2; Recurrent respiratory infections and epilepsyCACNA1C Long QT syndromeCACNA2D4 Abnormality of the eye; Retinal cone dystrophy-4 256 WO 2024/216206 PCT/US2024/024492 CAPNI Autosomal recessive spastic paraplegia-76; CAPN3 Absent Achilles reflex; Absent muscle fiber calpain-3; Arrhythmia; Calf muscle hypertrophy; Congenital muscular dystrophy; Contractures of the joints of the lower limbs; Difficulty walking; EMG: myopathic abnormalities; EMG; neuropathic changes; Elbow flexion contracture; Elevated serum creatine phosphokinase; Recessive limb-girdle muscular dystrophy type 2A; Limb-girdle muscle weakness; Limb-girdle muscular dystrophy; Migraine; Muscle weakness; Muscular diseases; Muscular dystrophy; Eosinophilic myositis; Paresthesia; Positive Romberg sign; Progressive spinal muscular atrophy; Shoulder girdle muscle weaknessCASK Mental retardation and microcephaly with pontine and cerebellar hypoplasiaCASP14 Congenital autosomal recessive ichthyosis- 12CASQ2 Catecholaminergic polymorphic ventricular tachycardia-2CASK Familial hypocalciuric hypercalcemia type 1; Inborn genetic diseases CASTPeeling skin with leukonychia, acral punctate keratoses, and knuckle pads; Cheilitis CAST, ERAP1Peeling skin with leukonychia, acral punctate keratoses, and knuckle pads; CheilitisCAT Acatalasemia; Japanese type acatalasiaCATSPERI Spermatogenic failure-7CAV1 Congenital generalized lipodystrophy type 3CAV3, SSUH2 Long QT syndrome CBLNoonan syndrome-like disorder with or without juvenile myelomonocytic leukemia CBSCystathionine beta-synthetase polymorphism; Classic homocystinuria;HomocystinuriaCC2D1A Psychosocial mental retardation; Autosomal recessive mental retardation-3 CC2D2AJoubert syndrome; Joubert syndrome-9; Meckel syndrome type 6; Meckel- Gruber syndromeCCBE1 Hennekam lymphangiectasia-lymphedema syndrome- 1CCDC103 Primary ciliary dyskinesiaCCDC28B Bardet-Biedl syndrome; Bardet-Biedl syndrome- 1CCDC39 Primary ciliary dyskinesia-14; Primary ciliary dyskinesiaCCDC40 Primary ciliary dyskinesia-15; Primary ciliary dyskinesia CCDC47Global developmental delay with dysmorphic features, woolly hair, liver dysfunction, and pruritus; Trichohepatoneurodevelopmental syndrome CCDC65Primary ciliary dyskinesia-27; Kartagener syndrome; Primary ciliary dyskinesiaCCDC78 Centronuclear myopathy -4CCDC88C Congenital hydrocephalus-1CCN6 Progressive pseudorheumatoid dysplasiaCCNH, RASA1 Capillary malformation; Arteriovenous malformation 257 WO 2024/216206 PCT/US2024/024492 CCNOPrimary ciliary dyskinesia-29; Kartagener syndrome; Primary ciliary dyskinesiaCCNQ Syndactyly-telecanthus-anogenital and renal malformations syndromeCD19 Common variable immunodeficiency-3CD247 Immunodeficiency due to defect in CD3-zetaCDS 6 Susceptibility to malaria; Platelet glycoprotein IV deficiencyCD46 Atypical hemolytic-uremic syndrome-2CD55 Cromer blood group system Dr(a-) phenotype; Protein-losing enteropathyCDC14A Autosomal recessive deafness-32; Rare genetic deafnessCDC73 Parathyroid adenoma; Parathyroid carcinoma CDH1 Blepharocheilodontic syndrome- 1; Lobular breast cancer; Endometrial carcinoma; Familial cancer of breast; Hereditary cancer-predisposing syndrome; Hereditary diffuse gastric cancer; Malignant tumor of prostate; Neoplasm of ovaryCDH11 Brachioskeletogenital syndrome CDH23 Autosomal recessive deafness-12; Inborn genetic diseases; Pituitary adenoma- 5 (multiple types); Rare genetic deafness; Usher syndrome type IDCDH23, C10orfl05 Rare genetic deafnessCDH23, CDH23-AS1Digenic Usher syndrome type ID/F; Usher syndrome type 1; Usher syndrome type ID CDH3Congenital hypotrichosis with juvenile macular dystrophy; EEM syndrome;Hypotrichosis with juvenile macular dystrophy; Macular dystrophy CDHRICone-rod dystrophy- 15; Leber congenital amaurosis; Retinal dystrophy;Retinitis pigmentosa-65CDK10 Al Kaissi syndrome CDK13Congenital heart defects, intellectual developmental disorder, and dysmorphic facial featuresCDK5RAP2 Primary autosomal recessive microcephaly -3 CDKL5Angelman syndrome-like; Atypical Rett syndrome; Early infantile epileptic encephalopathy -2; Epileptic encephalopathy; Inborn genetic diseases CDKN2AHereditary cancer-predisposing syndrome; Hereditary cutaneous melanoma; Melanoma-pancreatic cancer syndrome; NeoplasmCDSN, PSORS1C1 Peeling skin syndrome-1CEL Maturity-onset diabetes of the young type 8 CELA2ACoronary artery disease; Diabetes; Familial partial lipodystrophy-6;Hypertensive disorder; HypertriglyceridemiaCENPF Stromme syndrome CENPJ Congenital microcephaly; Intellectual disability; Perisylvian polymicrogyria; Primary autosomal recessive microcephaly; Primary autosomal recessive microcephaly- 1; Primary autosomal recessive microcephaly-6; Seckel syndrome-4; Type III lissencephaly 258 WO 2024/216206 PCT/US2024/024492 CEP 120 Joubert syndrome-31CEP152 Seckel syndrome CEP290 Abnormality of the kidney; Bardet-Biedl syndrome-14; Blindness; CEP290- related disorders; Cerebellar cyst; Cerebellar vermis hypoplasia; Global developmental delay; Hyperechogenic kidneys; Joubert syndrome; Joubert syndrome-5; Leber congenital amaurosis- 10; Meckel syndrome type 4; Meckel-Gruber syndrome; Nephronophthisis; Polycystic kidney dysplasia;Retinal dystrophy; Senior-Loken syndrome-6CEP290,C12orf29Bardet-Biedl syndrome-14; Joubert syndrome; Joubert syndrome-5; Meckel-Gruber syndrome; NephronophthisisCEP41 Joubert syndrome-15 CEP78Cone-rod degeneration; Cone-rod dystrophy and hearing loss-1; Sensorineural hearing loss CFAP251 Male infertility with teratozoospermia due to single gene mutation; Non- syndromic male infertility due to sperm motility disorder; Spermatogenic failure-18; Spermatogenic failure-33; Asthenozoospermia; Dysplasia of the mitochondrial sheath; Multiple morphologic abnormalities of the sperm flagellum CFAP410Axial spondylometaphyseal dysplasia; Retinal dystrophy with or without macular staphylomaCFAP43 Spermatogenic failure- 19CFAP44 Spermatogenic failure-20CFHR5 CFHR5 deficiency CFTR Bronchiectasis with or without elevated sweat chloride-1; CFTR-related disorders; Congenital bilateral aplasia of vas deferens from CFTR mutation; Cystic fibrosis; Hereditary pancreatitis; Inborn genetic diseases; Ataluren responseCFTR, CFTR- ASICFTR-related disorders; Congenital bilateral aplasia of vas deferens from CFTR mutation; Cystic fibrosis CFTR, LOCI 11674472 Bronchiectasis with or without elevated sweat chloride-1; CFTR-related disorders; Congenital bilateral aplasia of vas deferens from CFTR mutation; Cystic fibrosis; Hereditary pancreatitis CFTR, LOCI 11674475 Bronchiectasis with or without elevated sweat chloride-1; CFTR-related disorders; Congenital bilateral aplasia of vas deferens from CFTR mutation; Cystic fibrosis; Hereditary pancreatitis; Inborn genetic diseases; ataluren responseCFTR, LOCI 11674477 Cystic fibrosis CFTR, LOCI 13633877 Bronchiectasis with or without elevated sweat chloride-1; CFTR-related disorders; Congenital bilateral aplasia of vas deferens from CFTR mutation; Cystic fibrosis; Hereditary pancreatitis CFTR, LOC113664106 Bronchiectasis with or without elevated sweat chloride-1; Congenital bilateral aplasia of vas deferens from CFTR mutation; Cystic fibrosis; Hereditary pancreatitis 259 WO 2024/216206 PCT/US2024/024492 CHD2CHD2-related disorder; Childhood-onset epileptic encephalopathy; History of neurodevelopmental disorder CHD7CHARGE association; Hypogonadism with anosmia; Hypogonadotropic hypogonadism-5 with or without anosmia CHEK2 Astrocytoma; B Lymphoblastic leukemia/lymphoma; Breast and colorectal cancer; Breast cancer; CHEK2-related cancer susceptibility; Colitis; Congenital heart defects; Diffuse intrinsic pontine glioma; Familial cancer of breast; Hematochezia; Hereditary breast and ovarian cancer syndrome; Hereditary cancer; Hereditary cancer-predisposing syndrome; Inflammation of the large intestine; Leiomyosarcoma; Li-Fraumeni syndrome; Li- Fraumeni syndrome-2; Malignant tumor of prostate; Neoplasm of the breast; Osteosarcoma; Ovarian neoplasms; Prostate cancer;Thromb ocy topeni aCHM Retinal dystrophyCHRDL1 MegalocorneaCHRNA1 Congenital myasthenic syndromeCHRNA2 Autosomal dominant nocturnal frontal lobe epilepsyCHRNA3 CHRNA3-related conditionCHRND Lethal multiple pterygium syndrome CHRNESlow-channel congenital myasthenic syndrome-4A; Congenital myasthenic syndrome-4C; Congenital slow-channel myasthenic syndromeCHRNE, C17orfl07Slow-channel congenital myasthenic syndrome-4A; Congenital myasthenic syndrome-4C; Fast-channel congenital myasthenic syndrome-4B CHRNGAutosomal recessive multiple pterygium syndrome; CHRNG-related disorders; Inborn genetic diseases; Lethal multiple pterygium syndromeCHST14 Musculocontractural type Ehlers-Danlos syndromeCHST3 Spondyloepiphyseal dysplasia with congenital joint dislocationsCHSY1 Temtamy preaxial brachydactyly syndromeCIBI Susceptibility to epidermodysplasia verruciformis-3CIITA Bare lymphocyte syndrome-2CKAP2L Filippi syndrome CLCNI Autosomal dominant intermediate Charcot-Marie-Tooth disease; Congenital myotonia; EMG: myopathic abnormalities; Muscular diseases; Autosomal dominant myotonia congenita; Autosomal recessive myotonia congenitaCLCN2 Leukoencephalopathy with ataxia; Juvenile myoclonic epilepsy-8 CLCN5X-linked recessive nephrolithiasis; X-linked recessive nephrolithiasis with renal failureCLDNI, CLDN16 Neonatal ichthyosis-sclerosing cholangitis syndromeCLIC5 Autosomal recessive deafnessCLN3 Juvenile neuronal ceroid lipofuscinosis; Neuronal ceroid lipofuscinosisCLN5, FBXL3 Neuronal ceroid lipofuscinosis; Neuronal ceroid lipofuscinosis-5 260 WO 2024/216206 PCT/US2024/024492 CLRNIRare genetic deafness; Retinal dystrophy; Retinitis pigmentosa; Usher syndrome type 3 ACNGA1, LOC101927157 Retinal dystrophy; Retinitis pigmentosa-49CNGB1 Retinal dystrophy; Retinitis pigmentosa; Retinitis pigmentosa-45 CNGB3 Abnormality of the eye; Achromatopsia; Achromatopsia-3; CNGB3-related disorders; Cone-rod dystrophy; Leber congenital amaurosis; Retinal dystrophy; Retinitis pigmentosa; Stargardt DiseaseCNNM2 Renal hypomagnesemia-6CNNM4 Jalili syndromeCNTNAP1 Lethal congenital contracture syndrome- 7CNTNAP2 Pitt-Hopkins-like syndrome- 1COASY Neurodegeneration with brain iron accumulation-6COG4 Congenital disorder of glycosylation type 2JCOG5 Congenital disorder of glycosylation type 21COG5, DUS4L,DUS4L-BCAP29 Congenital disorder of glycosylation type 21COL10A1 Schmid type metaphyseal chondrodysplasiaCOL11A1 F ibrochondrogenesi s- 1COL12A1 Ullrich congenital muscular dystrophy-2 COL17A1Junctional epidermolysis bullosa non-Herlitz type; Junctional epidermolysis bullosa localisata variantCOL18A1 Primary closed-angle glaucoma; Knobloch syndrome- 1COL18A1, SLC19A1Knobloch syndrome-1; Macular dystrophy; Retinal dystrophy; Retinitis pigmentosa COL1A1 Procollagen proteinase deficient Ehlers-Danlos syndrome; Infantile cortical hyperostosis; Recessive perinatal lethal osteogenesis imperfecta;Osteogenesis imperfecta type 1; Osteogenesis imperfecta type III; Dominant form osteogenesis imperfecta with normal sclerae; Postmenopausal osteoporosis COL1A2 COLlA2-related disorder; Autosomal recessive cardiac valvular form Ehlers-Danlos syndrome; Inborn genetic diseases; Osteogenesis imperfecta type 1 (classic type) COL2A1Spondyloperipheral dysplasia-short ulna syndrome; Stickler syndrome type COL3A1 Ehlers-Danlos syndrome; type 4COL4A3, MFF-DT Autosomal recessive Alport syndromeCOL4A5 X-linked recessive Alport syndrome- 1COL5A1 Classic type Ehlers-Danlos syndrome COL5A2Classic type Ehlers-Danlos syndrome; Ehlers-Danlos syndrome classic type-2COL6A1 Bethlem myopathy- 1 261 WO 2024/216206 PCT/US2024/024492 COL6A2 Bethlem myopathy- 1; Ullrich congenital muscular dystrophy- 1COL6A3 Bethlem myopathy- 1 COL7A1 Autosomal dominant dystrophic epidermolysis bullosa; Epidermolysis bullosa pruriginosa; Recessive dystrophic epidermolysis bullosa; Transient bullous dermolysis of the newbornCOL9A2 Stickler syndrome type 5COLEC10 3MC syndrome-3COLEC10, LOC101927513 3MC syndrome-3COLQ Congenital myasthenic syndrome; Endplate acetylcholinesterase deficiencyCOQ2 Primary coenzyme Q10 deficiency- 1COQ8A ADCK3-related disorders; Primary coenzyme Q10 deficiency -4COQ9 Primary coenzyme Q10 deficiency-5 COX15 Fatal infantile cardioencephalomyopathy due to cytochrome c oxidase deficiency-2; Leigh syndrome; Leigh syndrome due to mitochondrial complex IV deficiency CPCeruloplasmin belfast; Deficiency of ferroxidase; Systemic hemosiderosis due to aceruloplasminemiaCPAMD8 Anterior segment dysgenesis-8 CPLANEI Global developmental delay; Jaundice; Joubert syndrome; Joubert syndrome-1; Joubert syndrome-17; Orofaciodigital syndrome type 6; Typical Joubert syndrome MRI findingsCPOX CoproporphyriaCPSI Congenital hyperammonemia type 1CPSF1 Myopia-27 CPT2 Infantile carnitine palmitoyltransferase II deficiency; Lethal neonatal carnitine palmitoyltransferase II deficiency; Myopathic stress-induced carnitine palmitoyltransferase 11 deficiencyCRBI Leber congenital amaurosis-8CRB2 Focal segmental glomerulosclerosis-9; Steroid-resistant nephrotic syndromeCRIPT Ateleiotic dwarfism; Short stature with microcephaly and distinctive facies CRPPA Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A7; Limb-girdle muscular dystrophy-dystroglycanopathy type C7CRTAP Osteogenesis imperfecta type 7CRX Leber congenital amaurosis-7CRYAB Alpha-B crystallinopathy; Dilated cardiomyopathy-illCRYBA4, CRYBB1 Autosomal recessive congenital nuclear cataract-3CRYBB2 Cataract-3; Congenital cataractCSGALNACT1 Mild skeletal dysplasia with joint laxity and advanced bone ageCSPPI Joubert syndrome-21; Meckel-Gruber syndromeCSRP3 Cardiovascular phenotype 262 WO 2024/216206 PCT/US2024/024492 CSTBInborn genetic diseases; Progressive myoclonic epilepsy; Unverricht- Lundborg syndrome CTC1 Cerebroretinal microangiopathy with calcifications and cysts;Cerebroretinal microangiopathy with calcifications and cysts- 1; Dyskeratosis congenitaCTCF Autosomal dominant mental retardation-21 CTNNB1 Exudative vitreoretinopathy-7; Exudative vitreoretinopathy-1;Hepatocellular carcinoma; Inborn genetic diseases; Autosomal dominant mental retardation- 19CTNND1,TMX2-CTNND1 Blepharocheilodontic syndrome-2 CTNSCystinosis; Juvenile nephropathic cystinosis; Nephropathic cystinosis; Ocular cystinosisCTSD Neuronal ceroid lipofuscinosis- 10CTSH Variant of unknown significance CTU2Microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndromeCUBN Megaloblastic anemia due to inborn errors of metabolismCUL4B Cabezas type syndromic X-linked mental retardationCUL7 Three M syndrome- 1CWC27 Retinitis pigmentosa with or without skeletal anomaliesCWF19L1 Autosomal recessive spinocerebellar ataxia-17CYB5R3 Methemoglobinemia type 2CYBB X-linked chronic granulomatous diseaseCYP11B1,LOCI 06799833 Deficiency of steroid 11-beta-monooxygenase CYP17A1 Combined partial 17-alpha-hydroxylase/17/20-lyase deficiency; Complete combined 17-alpha-hydroxylase/17/20-lyase deficiency; Deficiency of steroid 17-alpha-monooxygenase CYP1B1 Anterior segment dysgenesis-6; CYP IB 1-related disorders; Congenital glaucoma; Congenital ocular coloboma; Primary congenital glaucoma-3 A;Primary infantile glaucoma-3B; Irido-corneo-trabecular dysgenesisCYP21A2, LOC106780800 Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiencyCYP21A2, TNXB, LOC 106780800 Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiencyCYP24A1 Infantile hypercalcemia- 1CYP26C1 Optic nerve hypoplasiaCYP27A1 Cholestanol storage diseaseCYP27B1 Vitamin D-dependent rickets type 1 263 WO 2024/216206 PCT/US2024/024492 CYP2C19CYP2C19-related poor metabolism of clopidogrel, mephenytoin, proguanil, amitriptyline, citalopram, clomipramine, and clopidogrel CYP2D6 CYP2D6-related poor metabolism of debrisoquine, deutetrabenazine, tamoxifen, tramadol, amitriptyline, antidepressants, clomipramine, desipramine, doxepin, imipramine, nortriptyline, tamoxifen, and trimipramineCYP2U1 Autosomal recessive spastic paraplegia-56CYP4F22 Autosomal recessive congenital ichthyosis-5CZ1P-ASNS, ASNS Asparagine synthetase deficiencyDBH Orthostatic hypotension- 1DBT Maple syrup urine disease; Maple syrup urine disease type 2 DCAF17Hypogonadism, alopecia, diabetes mellitus, mental retardation, and el ectrocardi ographi c abn ormal iti es DCLREICPartial severe combined immunodeficiency; Severe combined immunodeficiency due to DCLREIC deficiencyDCN Congenital stromal corneal dystrophyDDHDI Autosomal recessive spastic paraplegia-28DDRGKI Shohat type spondyloepimetaphyseal dysplasia DDX3X Delayed speech and language development; Global developmental delay; History of neurodevelopmental disorder; X-linked mental retardation- 102; Microcephaly DDX41Acute myeloid leukemia; Susceptibility to familial myeloproliferative, lymphoproliferative neoplasmsDEPDC5 DEPDC5-related disorder; Familial focal epilepsy with variable foci DESLimb-girdle muscular dystrophy type 2R; Myofibrillar myopathy- 1; Neuromuscular disease; Primary dilated cardiomyopathyDGKE Nephrotic syndrome type 7 DGUOK Hepatocerebral form mitochondrial DNA depletion syndrome due to DGUOK deficiency; Hepatocerebral mitochondrial DNA depletion syndrome-3; Autosomal recessive progressive external ophthalmoplegia with mitochondrial DNA deletions-4 DHCR7 2-3 toe syndactyly; Congenital microcephaly; Elevated 7- dehydrocholesterol; History of neurodevelopmental disorder; Inborn genetic diseases; Small for gestational age; Smith-Lemli-Opitz syndromeDHH 46, XY sex reversal type 7DHTKD1 2-aminoadipic 2-oxoadipic aciduriaDIAPH1 Seizures, cortical blindness, and microcephaly syndrome DICERIDICERI-related pleuropulmonary blastoma cancer predisposition syndrome; Hereditary cancer-predisposing syndromeDIPKIA, RPL5 Diamond-Blackfan anemia-6DLD Maple syrup urine disease type 3 264 WO 2024/216206 PCT/US2024/024492 DLG3 X-Linked mental retardation-90DLL3,PLEKHG2Leukodystrophy and acquired microcephaly with or without dystonia; Autosomal recessive spondylocostal dysostosis- 1DLX3 Amelogenesis imperfecta type IV; Tricho-dento-osseous syndromeDLX4 Orofacial cleft- 15DMD Becker muscular dystrophy; Duchenne muscular dystrophyDMPI Autosomal recessive hypophosphatemic vitamin D refractory ricketsDNAAF2 Primary ciliary dyskinesiaDNAAF4, DNAAF4-CCPG1 Primary ciliary dyskinesia DNAHlNon-syndromic male infertility due to sperm motility disorder;Spermatogenic failure-18DNAHl 1 Primary ciliary dyskinesia-7; Primary ciliary dyskinesiaDNAHl 7 Spermatogenic failure-39DNAH5 Primary ciliary dyskinesia-3; Primary ciliary dyskinesiaDNAI1 Kartagener syndrome; Primary ciliary dyskinesiaDNAI2 Primary ciliary dyskinesia-9; Primary ciliary dyskinesia DNAJB2Charcot-Marie-Tooth disease; Autosomal recessive distal spinal muscular atrophy-5DNAJC12 Mild non-BH4-deficient hyperphenylalaninemiaDNALl Primary ciliary dyskinesia- 16; Primary ciliary dyskinesiaDNM2 Intermediate dominant Charcot-Marie-Tooth disease-BDNMBP Cataract-48DOCK6 Adams-Oliver syndrome-2DOCK6, LOG 105372273 Adams-Oliver syndrome; Adams-Oliver syndrome-2 DOCK8Autosomal recessive hyperimmunoglobulin E recurrent infection syndrome; Inborn genetic diseases DOK7Congenital myasthenic syndrome; Inborn genetic diseases; Familial limb- girdle myasthenia; Pena-Shokeir syndrome type 1DOLK Congenital disorder of glycosylation type 1M DONSONMicrocephaly short stature and limb abnormalities; Microcephaly- micromelia syndromeDPY19L2 Spermatogenic failure-9DPYD Dihydropyrimidine dehydrogenase deficiency; Fluorouracil responseDRAM2 Cone-rod dystrophy 21; Retinal dystrophy DRCIPrimary ciliary dyskinesia-21; Kartagener syndrome; Primary ciliary dyskinesia DSC2 Arrhythmogenic right ventricular cardiomyopathy with mild palmoplantar keratoderma and woolly hair; Familial arrhythmogenic right ventricular dysplasia type 11DSC2, DSCAS Arrhythmogenic right ventricular cardiomyopathy type 11 265 WO 2024/216206 PCT/US2024/024492 DSG1 Focal, striate, or diffuse palmoplantar keratoderma-IDSG1,DSG1- ASICongenital erythroderma with palmoplantar keratoderma, hypotrichosis, and hyper-Ige DSG2 Arrhythmogenic right ventricular cardiomyopathy type 10; Cardiac arrest;Cardiomyopathy; Cardiovascular phenotype; Dilated cardiomyopathy;Hypertrophic cardiomyopathyDSG2, DSG2- ASI Dilated cardiomyopathy-IBBDSG4, DSG1- ASI Hypotrichosis-6 DSP Arrhythmogenic right ventricular cardiomyopathy type 8; Arrhythmogenic right ventricular dysplasia, cardiomyopathy; Cardiac arrest; Dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesis;Cardiovascular phenotype; DSP-related disorders; Dilated cardiomyopathy with woolly hair and keratoderma; Keratosis palmoplantaris striata-II; Left ventricular noncompaction cardiomyopathy; Lethal acantholytic epidermolysis bullosa; Long QT syndrome- 1; Primary dilated cardiomyopathy; Skin fragility-woolly hair-palmoplantar keratoderma syndrome; Ventricular tachycardia DSTAutosomal recessive epidermolysis bullosa simplex-2; Hereditary sensory and autonomic neuropathy type VI DUOX2 Congenital hypothyroidism; Familial thyroid dyshormonogenesis; Inborn genetic diseases; Nongoitrous euthyroid hyperthyrotropinemia; Thyroid dyshormonogenesis-6 DVL3Autosomal dominant Robinow syndrome- 1; Autosomal dominant Robinow syndrome-3 DYNC2H1 Jeune thoracic dystrophy; Short-rib polydactyly syndrome; Short-rib polydactyly syndrome type III; Short-rib thoracic dysplasia- 3 with or without polydactylyDYNC2I1 Short-rib thoracic dysplasia-8 with or without polydactyly DYNC2I2Jeune thoracic dystrophy; Short-rib thoracic dysplasia- 11 with or without polydactylyDYNC2LII Short-rib thoracic dysplasia-15 with polydactylyDYRKIA Autosomal dominant mental retardation-7 DYSF Autosomal recessive limb-girdle muscular dystrophy type 2B; Miyoshi muscular dystrophy-1; Distal myopathy with anterior tibial onset;Qualitative or quantitative defects of dysferlinECEL1 Distal arthrogryposis type 5D; Inborn genetic diseases ECHSIInborn genetic diseases; Mitochondrial short-chain enoyl-CoA hydratase deficiencyECM1 Lipid proteinosisEDA Hypohidrotic X-linked ectodermal dysplasiaEDARADD Autosomal recessive hypohidrotic/hair/tooth type Ectodermal dysplasia-1 lb 266 WO 2024/216206 PCT/US2024/024492 EDN3 Congenital central hypoventilation; Dominant Hirschsprung disease;Hirschsprung disease; Waardenburg syndrome; Waardenburg syndrome type 4BEDNRB, EDNRB-AS1 Rare genetic deafness EFEMP2Autosomal recessive cutis laxa type IB; Autosomal recessive cutis laxa type IAEHMTI Kleefstra syndrome- 1EIF2AK3 Wolcott-Rallison dysplasiaEIF2AK4 Autosomal recessive pulmonary venoocclusive disease-2EIF2B2 Leukoencephalopathy with vanishing white matter; OvarioleukodystrophyEIF2S3 MEHMO syndromeELN Inborn genetic diseases; Supravalvar aortic stenosisELOVL4 Retinal dystrophy; Stargardt Disease-3ELP1 Familial dysautonomiaELP2 ELP2-related disorders; Autosomal recessive mental retardation-58 EMDCardiovascular phenotype; X-linked Emery-Dreifuss muscular dystrophy- 1; Neuromuscular disease ENAMAmelogenesis imperfecta type IC; Autosomal dominant hypoplastic local amelogenesis imperfecta ENGHereditary hemorrhagic telangiectasia; Hereditary hemorrhagic telangiectasia type 1ENG, LOG 102723566 Hereditary hemorrhagic telangiectasia type 1EOGT Adams-Oliver syndrome; Adams-Oliver syndrome-4EPB42 Spherocytosis type 5EPCAM Congenital diarrhea with tufting enteropathy-5EPG5 Vici syndromeEPHB4 Capillary malformation-arteriovenous malformation-2EPHB4, SLC12A9 Capillary malformation-arteriovenous malformation-2EPOR Primary familial polycythemia due to EPO receptor mutation ERCC2Metachromatic leukodystrophy variant; Photosensitive trichothiodystrophy- 1; Xeroderma pigmentosum group DERCC3 Complementation group B Xeroderma pigmentosum ERCC4 Cockayne syndrome; Complementation group Q Fanconi anemia; Hutchinson-Gilford syndrome; Pre-B-cell acute lymphoblastic leukemia; XFE progeroid syndrome; Xeroderma pigmentosum group FERCC5, BIVM-ERCC5 Xeroderma pigmentosum; group G ERCC6Cerebrooculofacioskeletal syndrome-1; Cockayne syndrome-B; De Sanctis- Cacchione syndromeERCC8 Cockayne syndrome type A 267 WO 2024/216206 PCT/US2024/024492 ERCC8, ERCC8-AS1 Cockayne syndrome type AERCC8, NDUFAF2Cockayne syndrome type A; Nuclear type 10 mitochondrial complex deficiencyERF Craniosynostosis-1; Craniosynostosis-4 ERHAbnormality of finger; Coarse facial features; Global developmental delay; Unilateral renal agenesisESCO2 Roberts-SC phocomelia syndromeESRP1 Autosomal recessive deafness- 109ESRRB Rare genetic deafnessETFDH Multiple acyl-CoA dehydrogenase deficiencyETHEI Ethylmalonic encephalopathyEVC2 Curry-Hall syndrome; Ellis-van Creveld syndromeEXOSC3 Pontocerebellar hypoplasia type 1bEXPH5 Autosomal recessive nonspecific epidermolysis bullosa EXTISporadic chondrosarcoma; Multiple congenital exostosis; Multiple exostoses type 1EXT2 Multiple exostoses type 2EYAI Branchiootic syndrome; Melnick-Fraser syndrome; Rare genetic deafness EYA4Autosomal dominant deafness-10; Dilated cardiomyopathy-lJ; Rare genetic deafnessEYA4, TARID EYA4-related disordersEYS Retinal dystrophy; Retinitis pigmentosa; Retinitis pigmentosa-25F13A1 Factor XIII subunit A deficiencyF13B Factor XIII subunit B deficiencyF2 Congenital prothrombin deficiencyF5 Factor V deficiencyF8 Hereditary factor VIII deficiency disease F9Hereditary factor IX deficiency disease; X-linked thrombophilia due to factor IX defectFA2H Spastic paraplegia-35FAH Tyrosinemia type 1FAM161A Retinal dystrophy; Retinitis pigmentosa; Retinitis pigmentosa-28FAM20A Amelogenesis imperfecta type 1GFANCA Complementation group A Fanconi anemiaFANCB Complementation group B Fanconi anemia FANCCComplementation group C Fanconi anemia; Hereditary cancer-predisposing syndromeFANCC, AOPEPComplementation group C Fanconi anemia; Hereditary cancer-predisposing syndrome; Tracheoesophageal fistulaFANCF Complementation group F Fanconi anemia 268 WO 2024/216206 PCT/US2024/024492 FANCMFanconi anemia; Malignant germ cell tumor of ovary; Spermatogenic failure-28FARS2 Combined oxidative phosphorylation deficiency- 14 FARSBInterstitial lung and liver disease; Rajab interstitial lung disease with brain calcificationsFAS Autoimmune lymphoproliferative syndromeFAT4 Van Maldergem syndrome FBN1 Acromicric dysplasia; Acute aortic dissection; Cardiovascular phenotype;Autosomal dominant isolated ectopia lends; Familial thoracic aortic aneurysm; Familial thoracic aortic aneurysm and aortic dissection;Geleophysic dysplasia-2; Inborn genetic diseases; MASS syndrome; Marfan syndrome, Loeys-Dietz syndrome, Familial thoracic aortic aneurysms and dissections; Marfan lipodystrophy syndrome; Marfan syndrome; Stiff skin syndrome; Weill-Marchesani syndrome-2FBN1, LOCI 13939944Marfan syndrome; Loeys-Dietz syndrome; Familial thoracic aortic aneurysms and dissections; Marfan syndrome FBXL4Inborn genetic diseases; Mitochondrial DNA depletion syndrome;Encephalomyopathic type mitochondrial DNA depletion syndrome- 13FERMTI Kindler ’s syndromeFEZF1-AS1,FEZF1 Hypogonadotropic hypogonadism-22 with anosmiaFGD4 Charcot-Marie-Tooth disease; Charcot-Marie-Tooth disease type 4FGF16 Metacarpal 4-5 fusionFGF3 Deafness with labyrinthine aplasia microtia and microdontia (LAMM)FGG Congenital afibrinogenemia; Hypofibrinogenemia FHFumarase deficiency; Hereditary cancer-predisposing syndrome; Hereditary leiomyomatosis and renal cell cancer FIG4Charcot-Marie-Tooth disease type 41; Charcot-Marie-Tooth disease type 4;Yunis-Varon syndromeFKBP10 Bruck syndrome-1; Osteogenesis imperfecta type 12 FKBP14, FKBP14-AS1 Congenital muscular dystrophy; Ehlers-Danlos syndrome with progressive kyphoscoliosis, hearing loss, myopathy; Inborn genetic diseases; Joint hypermobility; Muscular hypotonia; Pes valgus; Thoracolumbar scoliosisFKRP Limb-girdle muscular dystrophy-dystroglycanopathy type C5 FKTN Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A4; Congenital muscular dystrophy-dystroglycanopathy without mental retardation type B4; FKTN-related disorders; Fukuyama congenital muscular dystrophy; Limb-girdle muscular dystrophy- dystroglycanopathy type C4; Walker-Warburg congenital muscular dystrophy FLCNHereditary cancer-predisposing syndrome; Multiple fibrofolliculomas; Primary spontaneous pneumothoraxFLG Atopic dermatitis-2; FLG-related disorder; Ichthyosis vulgarisFLNA Periventricular nodular heterotopia- 1 269 WO 2024/216206 PCT/US2024/024492 FLNB Spondylocarpotarsal synostosis syndrome FLNCFamilial hypertrophic cardiomyopathy-26; Dilated Cardiomyopathy;Dominant filamin C-related myofibrillar myopathy; Distal myopathy-4FLNC, FLNC- ASIFamilial hypertrophic cardiomyopathy-26; Dilated Cardiomyopathy;Dominant filamin C-related myofibrillar myopathy; Distal myopathy-4FLT4 Congenital heart defects-?FMRI Intellectual disabilityFOXF1 Persistent fetal circulation syndromeFOXG1 History of neurodevelopmental disorder; Congenital variant Rett syndromeFOXL2 Blepharophimosis, ptosis, epicanthus inversus type 1 FOXN1 Autosomal dominant infantile T-cell lymphopenia with or without nail dystrophy; T-cell immunodeficiency, congenital alopecia, and nail dystrophy FOXPIMental retardation with language impairment and with or without autistic featuresFOXREDI Leigh syndrome; Nuclear type 1 mitochondrial complex 1 deficiencyFRASI Fraser syndrome- 1 FREM2Isolated unilateral or bilateral cryptophthalmos; Fraser syndrome-2; Fraser syndrome- 1FSHB Hypogonadotropic hypogonadism-24 without anosmiaFSIP2 Spermatogenic failure-34FSIP2, FSIP2-ASI Spermatogenic failure-34FTCD Glutamate formiminotransferase deficiencyFTSJI X-linked mental retardation-9FUCA1 FucosidosisFYCOl Cataract- 18FZD4, PRSS23 Exudative retinopathy; Familial exudative vitreoretinopathy G6PCGlycogen storage disease; Glycogen storage disease due to glucose-6- phosphatase deficiency type IAGAA Glycogen storage disease type II; Pompe diseaseGABRA1 Juvenile myoclonic epilepsy-5; Early infantile epileptic encephalopathy- 19GABRA6 GABRA6-related disorderGALC Galactosylceramide beta-galactosidase deficiencyGALM Galactosemia-IVGALNS MPS-IV-A mucopolysaccharidosis; Morquio syndromeGALT Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase GAMTCerebral creatine deficiency syndrome; Deficiency of guanidinoacetate methyltransferaseGAREM2, HADHALong-chain 3-hydroxyacyl-CoA dehydrogenase deficiency; Mitochondrial trifunctional protein deficiencyGATAl Acute megakaryoblastic leukemia 270 WO 2024/216206 PCT/US2024/024492 GATA3 Hypoparathyroidism-deafness-renal disease syndrome GATA6 Abnormality of cardiovascular system morphology; Congenital diaphragmatic hernia; Pancreatic agenesis and congenital heart disease; Persistent truncus arteriosus GATAD1, PEX1Deafness, enamel hypoplasia, and nail defects; Zellweger peroxisome biogenesis disorder 1AGATAD2B GATAD2B-related disorder; Autosomal dominant mental retardation- 18 GBA Acute neuronopathic Gaucher ’s disease; Gaucher disease; Gaucher disease type 3C; Gaucher ’s disease type 1; Subacute neuronopathic Gaucher ’s diseaseGBA, LOG 106627981 Gaucher disease type 1; Perinatal lethal Gaucher ’s disease GBEIClassic hepatic glycogen storage disease type IV; Fatal perinatal neuromuscular glycogen storage disease-IVGCDH Glutaric aciduria type 1GCH1 Dystonia- 5 GCKMaturity onset diabetes mellitus in young; Maturity-onset diabetes of the young type 2GDAPI Recessive intermediate Charcot-Marie-Tooth disease type 4AGDF1, CERS1 Heterotaxi aGDF9 Premature ovarian failure- 14GFER Mitochondrial diseases GHRLaron syndrome with elevated serum GH-binding protein; Laron-type isolated somatotropin defectGJBI Charcot-Marie-Tooth Neuropathy-X; Charcot-Marie-Tooth disease GJB2 Bilateral conductive hearing impairment; Bilateral sensorineural hearing impairment; GJB2-related disorders; Dominant digenic deafness- GJB2/GJB3; Digenic deafness-GJB2/GJB6; Hearing impairment; Autosomal dominant hearing loss-3 A; Hystrix-like ichthyosis with deafness; Inborn genetic diseases; Autosomal dominant keratitis ichthyosis and deafness syndrome; Recessive keratitis-ichthyosis-deafness syndrome; Knuckle pads, deafness, and leukonychia syndrome; Mutilating keratoderma; Autosomal recessive nonsyndromic hearing loss- 1 A; Nonsyndromic hearing loss and deafness; Palmoplantar keratoderma- deafness syndrome; Rare genetic deafnessGJB3 Autosomal dominant deafness-2BGLA, RPL36A- HNRNPH2 Fabry disease GLB1 GLBl-related disorders; GMI gangliosidosis; GMI gangliosidosis type 2; GMI gangliosidosis type 3; GMI-gangliosidosis type 1 with cardiac involvement; Infantile GMI gangliosidosis; MPS-IV- BmucopolysaccharidosisGLDC Non-ketotic hyperglycinemiaGLDN Lethal congenital contracture syndrome- 11 271 WO 2024/216206 PCT/US2024/024492 GLI3Greig cephalopolysyndactyly syndrome; Pallister-Hall syndrome; Postaxial polydactyly type Al, B; Preaxial polydactyly-4GLIS3 Neonatal diabetes mellitus with congenital hypothyroidismGLMN Glomuvenous malformationsGERAl Hyperekplexia-1 GNASProgressive osseous heteroplasia; Pseudohypoparathyroidism; Pseudop seudohy poparathy roi di smGNAT2 Achromatopsia-4 GNB5 Intellectual developmental disorder with cardiac arrhythmia; Language delay and attention deficit-hyperactivity disorder, cognitive impairment with or without cardiac arrhythmiaGNPAT Rhizomelic chondrodysplasia punctata type 2 GNPTAB GNPTAB-related disorders; Inborn genetic diseases; Mucolipidosis-III Alpha, Beta; Mucolipidosis; Mucolipidosis type II; Pseudo-Hurler polydystrophyGNPTG Mucolipidosis; Mucolipidosis type III GammaGORAB Geroderma osteodysplasticaGOSR2, LRRC37A2 Progressive myoclonic epilepsyGPC3 Simpson-Golabi-Behmel syndrome; Wilms tumor-1GPC4 Keipert syndromeGPC6 Autosomal recessive omodysplasiaGPC6, GPC6- AS2 Autosomal recessive omodysplasia GPINonspherocytic hemolytic anemia due to glucose phosphate isomerase deficiencyGPNMB Primary localized cutaneous amyloidosis-3GPR143 Ocular albinism type 1GPR179 Congenital stationary night blindness type IE; Retinal dystrophy GPSM2Chudley-McCullough syndrome; GPSM2-related disorders; Rare genetic deafnessGRHL2 Autosomal dominant deafness-28GRHL3 Van der Woude syndrome-2GRHPR Nephrocalcinosis; Nephrolithiasis; Primary hyperoxaluria type IIGRIN2B Autosomal dominant mental retardation-6GRIP! Fraser syndrome-3GRN Frontotemporal dementiaGRXCRI Autosomal recessive deafness-25; Rare genetic deafnessGSDME Autosomal dominant deafness-5GUCY2C, C12orf60 Meconium ileusGUSB Mucopolysaccharidosis type 6; Mucopolysaccharidosis type 7GYG1 Glycogen storage disease XV; Polyglucosan body myopathy-2 272 WO 2024/216206 PCT/US2024/024492 GYSI Muscle glycogen storage disease-0 GYS2Glycogen storage disease; Glycogen storage disease due to hepatic glycogen synthase deficiencyGZF1 Joint laxity, short stature, and myopiaHl -4 Inborn genetic diseases; Rahman syndromeH6PD Cortisone reductase deficiency- 1 HADHAHADHA-related disorders; Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency; Mitochondrial trifunctional protein deficiency HADHA,GAREM2 HADHA-related disorders; Inborn genetic diseases; LCHAD deficiency; LCHAD deficiency with maternal acute fatty liver of pregnancy; Long- chain 3-hydroxyacyl-CoA dehydrogenase deficiency; Mitochondrial trifunctional protein deficiencyHAXI Autosomal recessive severe congenital neutropenia-3HBA2, LOC106804612 Alpha plus thalassemia HBB,LOC 106099062, LOC107133510 Anemia; Beta thalassemia major; Beta-plus-thalassemia; Beta-thalassemia; Familial erythrocytosis-6; Fetal hemoglobin quantitative trait locus 1; HBB- related disorders; Hb SS disease; Heinz body anemia; Hemoglobin E; Hemoglobin E disease; Hemoglobin E, Beta thalassemia disease;Hemoglobin M disease; Hemoglobinopathy; Resistance to malaria; Susceptibility to malaria; Alpha thalassemia; Dominant inclusion body type beta thalassemiaHBB, LOC107133510, LOC 110006319 Beta thalassemiaHCN4 Brugada syndrome-8; Autosomal dominant sick sinus syndrome-2HEXA Inborn genetic diseases; Tay-Sachs diseaseHEXB Infantile Sandhoff diseaseHFM1 Premature ovarian failure-9HGD Alkaptonuria HGSNATMPS-III-C mucopolysaccharidosis; Retinitis pigmentosa-73; Sanfilippo syndromeHIVEP2 Angelman syndrome-like; Autosomal dominant mental retardation-43HIV Hemochromatosis type 2AHECS Holocarboxylase synthetase deficiencyHMCN1 Age-related macular degeneration- 1HMGB3 Syndromic microphthalmia- 13HMGCL Deficiency of hydroxymethylglutaryl-CoA lyase HNF1A Clear cell carcinoma of kidney; Insulin-dependent diabetes mellitus; Type diabetes mellitus-20; Familial hepatic adenomas; Maturity onset diabetes mellitus in young; Maturity-onset diabetes of the young type 3 HNF1BFamilial hypoplastic renal cysts and diabetes syndrome; Glomerulocystic kidneyHNRNPK Au-Kline syndrome 273 WO 2024/216206 PCT/US2024/024492 HNRNPU Epileptic encephalopathy HOXA1Athabaskan brainstem dysgenesis syndrome; Bosley-Salih-Alorainy syndromeHOXA11 Radioulnar synostosis with amegakaryocytic thrombocytopenia- 1HOXD13 Synpolydactyly- 1 HPGDHPGD-related disorders; Autosomal recessive primary hypertrophic osteoarthropathy- 1HPSI Hermansky-Pudlak syndrome; Hermansky-Pudlak syndrome- 1HPS5 Hermansky-Pudlak syndrome; Hermansky-Pudlak syndrome-5HPS6 Hermansky-Pudlak syndrome; Hermansky-Pudlak syndrome-6HPSE2 Urofacial syndrome- 1HR Atrichia with papular lesionsHSD17B10 HSD10 diseaseHSD17B4 Bifunctional peroxisomal enzyme deficiency; Perrault syndromeHSPA9 Even-plus syndrome; Sideroblastic anemia-4 HSPB1Charcot-Marie-Tooth disease; Charcot-Marie-Tooth disease axonal type 2F; Distal hereditary motor neuronopathy type 2BHSPG2 Lethal Kniest-like syndrome; Schwartz-Jampel syndromeHYALI Deficiency of hyaluronoglucosaminidaseHYDIN Primary ciliary dyskinesia-5ICAM4 Landsteiner-Wiener phenotypeIDS MPS-II mucopolysaccharidosisIDS,LOC106050102 MPS-II mucopolysaccharidosis IDUAHurler syndrome; MPS-I-H/S mucopolysaccharidosis; MPS-I-S mucopolysaccharidosis type 1IDUA, SLC26A1Hurler syndrome; MPS-I-H/S mucopolysaccharidosis; MPS-I-S mucopolysaccharidosis type 1IFIH1 Aicardi-Goutieres syndrome-7; Singleton-Merten syndrome- 1 IFNGRIDisseminated atypical mycobacterial infection; IFN-gamma receptor deficiency; Immunodeficiency-27B; Inherited immunodeficiency diseasesIFNGR2 Immunodefi ci ency -2 8IFT140 Retinitis pigmentosa-80 IFT140, LOC105371046 Jeune thoracic dystrophy; Joubert syndrome with Jeune asphyxiating thoracic dystrophy; Renal dysplasia, cerebellar ataxia, skeletal dysplasia, and retinal pigmentary dystrophyIFT172 Short-rib thoracic dysplasia- 10 with or without polydactyly IFT52Short Rib Polydactyly Syndrome; Short-rib thoracic dysplasia-16 with or without polydactylyIGF1 Growth delay due to insulin-like growth factor type 1 deficiencyIGFIR Inborn genetic diseasesIGFALS Acid-labile subunit deficiencyIGHM Non-Bruton type agammaglobulinemia 274 WO 2024/216206 PCT/US2024/024492 IGHMBP2 Autosomal dominant distal hereditary motor neuropathy; Charcot-Marie- Tooth disease axonal type 2S; Distal spinal muscular atrophy; Inborn genetic diseases; Autosomal recessive distal spinal muscular atrophy- 1IGLL1 Autosomal recessive agammaglobulinemia- 2IGSF1 Central hypothyroidism and testicular enlargementIGSF3 Lacrimal duct defect IKBKGEctodermal dysplasia and immunodeficiency- 1; Immunodeficiency without anhidrotic ectodermal dysplasia; Incontinentia pigmentiIL12B Immunodefi ci ency -29ILI2RB1 Immunodefi ci ency -3 0IL2RB Ichthyosis IL2RGX-linked combined immunodeficiency; X-linked severe combined immunodeficiencyIL36RN Generalized pustular psoriasis IL7RAutosomal recessive T cell-negative, B cell-positive, NK cell-positive severe combined immunodeficiencyINPPSE Retinal dystrophyINPPL1 OpsismodysplasiaINTU Mohr syndrome; Orofaciodigital syndrome- 17IQCBI Renal dysplasia and retinal aplasiaIQCE Postaxial polydactyly type A7IQSEC2 Mental retardation; X-linked severe intellectual deficiency- 1 IRAK4Immunodeficiency due to interleukin-1 receptor-associated kinase-deficiency IRF2BPLNeurodevelopmental disorder; Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizuresIRF6 Van der Woude syndromeIRS4 Congenital nongoitrous hypothyroidism-9ISCA2 Multiple mitochondrial dysfunctions syndrome-4ISG15 Immunodeficiency -38 with basal ganglia calcificationITGA7 Congenital muscular dystrophy due to integrin alpha-7 deficiencyITGB2 Leukocyte adhesion deficiencyITGB4 Epidermolysis bullosa junctionalis with pyloric atresia ITPAEarly infantile epileptic encephalopathy-35; Inosine triphosphatase deficiencyITPRI Gillespie syndromeIVD Isovaleric acidemia; Isovaleryl-CoA dehydrogenase deficiency type IIIJAGI Alagille syndrome-1; Arteriohepatic dysplasia; Malformation of heart JAK3 Autosomal recessive T cell-negative, B cell-positive, NK cell-negative severe combined immunodeficiency; Severe combined immunodeficiency disease KAT6AHistory of neurodevelopmental disorder; Autosomal dominant mental retardation-32KAT6B SBBYS type blepharophimosis-intellectual disability syndrome 275 WO 2024/216206 PCT/US2024/024492 KAT6B, DUPD1SBBYS type blepharophimosis-intellectual disability syndrome;Genitopatellar syndrome; Inborn genetic diseasesKATNIP Joubert syndrome-26KCNAI Episodic ataxia type 1KCNA5 Familial atrial fibrillation-7KCNC1 Progressive myoclonic epilepsy-7KCNE1 Long QT syndrome KCNH2 Cardiac arrhythmia; Cardiovascular phenotype; Congenital long QT syndrome; Long QT syndrome; Digenic long QT syndrome- 1/2; Long QT syndrome-2KCNK18 Migraine with or without aura- 13 KCNQI Cardiac arrhythmia; Cardiovascular phenotype; Congenital long QT syndrome; Jervell and Lange-Nielsen syndrome; Jervell and Lange-Nielsen syndrome-1; KCNQI-related disorders; Long QT syndrome LQT1 subtype; Long QT syndrome- 1; Rare genetic deafness; Romano-Ward syndromeKCNQ1-AS1, KCNQI Jervell and Lange-Nielsen syndrome- 1KCNQI, KCNQI-ASI Cardiovascular phenotype; Long QT syndrome; Long QT syndrome- 1KCNQI, KCNQI on Congenital long QT syndrome; Long QT syndrome LQT1 subtype KCNQ2 Benign familial neonatal seizures-1; Early infantile epileptic encephalopathy; Early infantile epileptic encephalopathy-7; Epileptic encephalopathy; Inborn genetic diseases; SeizuresKCNQ3 Intellectual disability; SeizuresKCNQ4 Autosomal dominant nonsyndromic deafness-2A KCNTIEarly infantile epileptic encephalopathy- 14; Nocturnal frontal lobe epilepsy-5 KCNV2Cone dystrophy with supernormal rod response; Progressive cone dystrophy without rod involvement; Retinal dystrophy; Stargardt diseaseKDM5B Autosomal recessive intellectual disability-65KDM5C X-linked Claes-Jensen type syndromic mental retardationKDM6A Kabuki syndrome-2KERA Cornea plana-2KHDC3L Recurrent hydatidiform mole-2 KIAA0586 Congenital cerebellar hypoplasia; Intellectual disability; Joubert syndrome; Joubert syndrome-23; Retinal dystrophy; Rod-cone dystrophy; Short-rib thoracic dysplasia-14 with polydactylyKIAA0753 Orofaciodigital syndrome-XVKIAA0825 Postaxial polydactyly type A10; Postaxial polydactyly type AlKIAA1549 Retinitis pigmentosa-86 KIF11Microcephaly with or without chorioretinopathy, lymphedema, and mental retardationKIF7 Acrocallosal syndrome; Joubert syndrome- 12 276 WO 2024/216206 PCT/US2024/024492 KIFBP Goldberg-Shprintzen megacolon syndromeKISSIR Hypogonadotropic hypogonadism-8 without anosmiaKIZ Retinitis pigmentosa-69KMT2A Wiedemann-Steiner syndromeKMT2B Childhood-onset dystonia-28KMT2C Kleefstra syndrome due to a point mutationKMT2D CHARGE association; Kabuki syndrome; Kabuki syndrome- 1 KMT2EEpilepsy; Leukoencephalopathy; Macrocephalus; O’Donnell-Luria-Rodan syndrome; Intellectual deficiencyKPTN Autosomal recessive mental retardation-41 KRITICavernous malformations of CNS and retina; Cerebral cavernous malformation; Cerebral cavernous malformations- 1KRT1 Curth-Macklin type ichthyosis histrix;KRT10 Bullous ichthyosiform erythrodermaKRT10, TMEM99 Bullous ichthyosiform erythrodermaKRT14 Autosomal recessive epidermolysis bullosa simplexKRT5 Dowling-Degos disease- 1KRT6A Pachyonychia congenita-3KRT85 ‘Pure ’ hair-nail type ectodermal dysplasia KYNUCongenital NAD deficiency disorder; Vertebral, cardiac, renal, and limb defects syndrome-2LICAM MASA syndrome; Spastic paraplegiaL2HGDH L-2-hydroxy glutaric aciduriaLACCI Juvenile arthritis LAMA2Inborn genetic diseases; Laminin alpha 2-related dystrophy; Merosin deficient congenital muscular dystrophyLAMAS Junctional epidermolysis bullosa gravis of HerlitzLAMA4 Dilated cardiomyopathy- 1JJ LAMBSAmelogenesis imperfecta type 1A; Non-Herlitz type junctional epidermolysis bullosa; Junctional epidermolysis bullosa gravis of Herlitz LAMC2Non-Herlitz type junctional epidermolysis bullosa; Junctional epidermolysis bullosa gravis of Herlitz LAMP2Cardiomyopathy; Danon disease; Hypertrophic cardiomyopathy; Primary dilated cardiomyopathy LARGE 1Congenital muscular dystrophy-dystroglycanopathy with mental retardation type B6 LBR Disproportionate short stature; Femoral bowing; Pelger-Huet anomaly;Regressive spondylometaphyseal dysplasia; Retrognathia; Rhizomelic arm shortening; Rhizomelic leg shortening; Short long boneLDBS Cardiomyopathy; ZASP-related myofibrillar myopathy LDLRFamilial hypercholesterolemia; Familial hypercholesterolemia- 1; Homozygous familial hypercholesterolemiaLDLRAP1 Familial hypercholesterolemia-4 277 WO 2024/216206 PCT/US2024/024492 LEP Leptin deficiency or dysfunctionLFNG Autosomal recessive spondylocostal dysostosis-3LGH Familial temporal lobe epilepsy-1LHFPL5 Rare genetic deafness LHX3Non-acquired combined pituitary hormone deficiency with spine abnormalitiesLIFR Stuve-Wiedemann syndromeLIG4 LIG4-related disorders; Lig4 syndromeLIPA Lysosomal acid lipase deficiencyLIPE Familial partial lipodystrophy-6LIPE, LIPE- ASI, LOC101930071 Familial partial lipodystrophy-6 LIPHHypotrichosis-7; Autosomal recessive woolly hair-2 with or without hypotrichosisLIPN Autosomal recessive congenital ichthyosis-8LMBR1 Acheiropodia LMBRDIInborn genetic diseases; Methylmalonic aciduria and homocystinuria type cblF LMNACardiovascular phenotype; Charcot-Marie-Tooth disease type 2; Primary dilated cardiomyopathyLMOD3 Nemaline myopathy- 10LMXIB Nail-patella syndromeLOG 100507346,PTCHI Gorlin syndrome; MedulloblastomaLOC101927055, TTNDilated cardiomyopathy 1G; Limb-girdle muscular dystrophy type 2J; Primary dilated cardiomyopathyLOC101927157, CNGA1 Retinitis pigmentosa; Retinitis pigmentosa-49LOC101927188,LAMAl Poretti-Boltshauser syndromeLOC 102723 566, ENG Hereditary hemorrhagic telangiectasia type 1LOC 106694316,MPO Myeloperoxidase deficiencyLOC 110006319,HBB,LOC107133510 Beta thalassemiaLOXHD1 Autosomal recessive deafness-77; Rare genetic deafnessLPL Hyperlipoproteinemia type 1 LRATLeber congenital amaurosis; Leber congenital amaurosis- 14; Early-onset severe retinal dystrophy; Juvenile LRAT-related retinitis pigmentosaLRBA Common variable immunodeficiency-8 with autoimmunityLRIT3 Congenital stationary night blindness type IF 278 WO 2024/216206 PCT/US2024/024492 LRP4 Cenani-Lenz syndactyly syndrome LRP5Exudative vitreoretinopathy-4; Autosomal dominant familial exudative vitreoretinopathyLRP6 Selective tooth agenesis-7LRPAP1 Autosomal recessive myopia-23; Rare isolated myopiaLRPPRC Saguenay-Lac-Saint-Jean type congenital lactic acidosisERSAMI Charcot-Marie-Tooth disease type 2PERTOMT Autosomal recessive deafness-63; Rare genetic deafnessLTBP2 Congenital glaucoma; MicrospherophakiaLTBP3 Dental anomalies and short stature LTBP4Cutis laxa with severe pulmonary, gastrointestinal, and urinary abnormalitiesLYRM7 Nuclear type 8 Mitochondrial complex III deficiencyLZTFL1 Bardet-Biedl syndrome-17LZTR1 Noonan syndrome-2; Schwannomatosis-2MAB21L1, NBEA Cerebellar, ocular, craniofacial, and genital syndrome MAFBDuane retraction syndrome-2; Duane retraction syndrome-3 with or without deafness; Duane syndrome type 1; Duane syndrome type 3MAGED2 Transient antenatal Bartter syndrome type 5MAGEE2 Inborn genetic diseases; Schaaf-Yang syndrome MAGTIX-Linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasiaMAK Retinal dystrophyMAN2B1 Deficiency of alpha-mannosidaseMANBA Beta-D-mannosidosisMAP2K2 RasopathyMAPRE2 Congenital symmetric circumferential skin creases-2MARVELD2 Autosomal recessive neurosensory deafness-49; Rare genetic deafnessMAX Hereditary cancer-predisposing syndromeMBD5 Autosomal dominant mental retardation- 1MC2R ACTH resistanceMC4R Monogenic diabetes; Obesity; SchizophreniaMCCC1 Methylcrotonyl-CoA carboxylase 1 deficiency-3MCCC2 Methylcrotonyl C0A carboxylase 2 deficiency-3MCM5 Meier-Gorlin syndrome-8MCM8 Premature ovarian failure- 10MCOLNI Mucolipidosis type IV MCPH1Abnormality of brain morphology; Primary autosomal recessive microcephaly- 1 279 WO 2024/216206 PCT/US2024/024492 MECP2 Angelman syndrome; Atypical Rett syndrome; X-linked susceptibility to autism-3; Delayed gross motor development; Delayed speech and language development; Developmental regression; Encephalopathy; Global developmental delay; History of neurodevelopmental disorder; Inborn genetic diseases; Intellectual disability; Loss of ability to walk; X-linked syndromic mental retardation-13; Rett syndrome; Severe neonatal-onset encephalopathy with microcephaly; Smith-Magenis Syndrome-like; Lubs type syndromic X-linked intellectual disability; Neonatal severe mental retardation; Syndromic Rett syndrome- 13 MED12Cardiovascular phenotype; FG syndrome-1; History of neurodevelopmental disorder MED13LMental retardation and distinctive facial features with or without cardiac defects MED25 Broad-based gait; Charcot-Marie-Tooth disease type 2; Decreased body weight; Failure to thrive; Generalized hypotonia; Impaired distal proprioception; Sensory ataxia; Sensory ataxic neuropathy; Sensory neuropathy MEF2CMEF2C-related disorder; Mental retardation, epilepsy, and stereotypic movements and/or cerebral malformationsMEFV Familial Mediterranean fever MENIHereditary cancer-predisposing syndrome; Somatic lipoma; Multiple endocrine neoplasia type 1MERTK Retinitis pigmentosa-38MESD Osteogenesis imperfecta type XXMETTL23 Inborn genetic diseases; Autosomal recessive mental retardation-44MFN2 Charcot-Marie-Tooth disease type 2MFRP, C1QTNF5 Isolated microphthalmia-5; Nanophthalmos-2MFSD8 Neuronal ceroid lipofuscinosis-7MIP Cataract- 15 (multiple types)MIR6886,LDLRFamilial hypercholesterolemia; Familial hypercholesterolemia- 1; Homozygous familial hypercholesterolemia MIFFColoboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness; Rare genetic deafness; Waardenburg syndrome type 2AMKRN3 Central precocious puberty-2 MKSIJoubert syndrome; Joubert syndrome-28; Meckel syndrome type 1; Meckel- Gruber syndromeMLC1 Megalencephalic leukoencephalopathy with subcortical cysts- 1 MLH1 Carcinoma of colon; Colon cancer; Hereditary cancer-predisposing syndrome; Hereditary nonpolyposis colon cancer; Lynch syndrome; Lynch syndrome-I; Lynch syndrome-II; Muir-Torre syndrome; Turcot syndromeMLH3 Hereditary nonpolyposis colorectal cancer type 7MLYCD Deficiency of malonyl-CoA decarboxylase MMAAMethylmalonic acidemia; Vitamin B12-responsive methylmalonic acidemia type cblA 280 WO 2024/216206 PCT/US2024/024492 MMABMethylmalonic acidemia; Vitamin B12-responsive methylmalonic acidemia type cblB MMACHC Disorders of intracellular cobalamin metabolism; Digenic methylmalonic aciduria and homocystinuria clbC type; Methylmalonic acidemia with homocystinuria; Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency MME Charcot-Marie-Tooth disease axonal type 2T; Congenital membranous nephropathy due to fetomaternal anti-neutral endopeptidase alloimmunization MMUTMethylmalonic acidemia; Methylmalonic aciduria due to methyl malonyl- CoA mutase deficiencyMOCS2 Complementation group B molybdenum cofactor deficiency MPDZCongenital hydrocephalus; Congenital hydrocephalus-2 with or without brain or eye anomaliesMPL Congenital amegakaryocytic thrombocytopenia; Essential thrombocytemiaMPLKIP Nonphotosensitive trichothiodystrophy- 1MPO Myeloperoxidase deficiencyMP VI7 Navajo neurohepatopathyMPZ Charcot-Marie-Tooth diseaseMPZL2 Autosomal recessive deafness- 111MREll Hereditary cancer-predisposing syndrome MSH2 Carcinoma of colon; Colon cancer; Glioblastoma; Hereditary cancer- predisposing syndrome; Hereditary nonpolyposis colon cancer; Lynch syndrome; Lynch syndrome-I; Malignant tumor of ascending colon; Malignant tumor of sigmoid colon; Muir-Torre syndrome; Ovarian neoplasms; Turcot syndrome MSH6 Endometrial carcinoma; Hereditary cancer-predisposing syndrome;Hereditary nonpolyposis colon cancer; Hereditary nonpolyposis colorectal cancer type 5; Hereditary nonpolyposis colorectal carcinoma; Lynch syndrome; Lynch syndrome-I; Turcot syndrome MSTOlMitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndromeMSX2 Parietal foramina- 1 MTFMT Abnormal facial shape; Combined oxidative phosphorylation deficiency- 15; Cytochrome C oxidase-negative muscle fibers; Decreased activity of mitochondrial complex I; Inability to walk by childhood/adolescence; Leigh syndrome; Nuclear type 27 Mitochondrial complex 1 deficiency;Mitochondrial oxidative phosphorylation disorder; Poor speech; Short stature MTHFD1Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemiaMTM1 Severe X-linked myotubular myopathy MTRR Disorders of intracellular cobalamin metabolism; Homocystinuria without methylmalonic aciduria; CblE complementation type homocystinuria- megaloblastic anemia due to defect in cobalamin metabolism 281 WO 2024/216206 PCT/US2024/024492 MTTP Abetalipoproteinaemia MUTYH Carcinoma of colon; Colon cancer; Familial colorectal cancer; Hereditary cancer-predisposing syndrome; MUTYH-associated polyposis; MYH- associated polyposis; Neoplasm of stomach; Pilomatrixoma MVKHyperimmunoglobulin D with periodic fever; Mevalonic aciduria; Disseminated superficial actinic type porokeratosis-3 MYBPC3 Asymmetric septal hypertrophy; Cardiomyopathy; Cardiovascular phenotype; Dyspnea; Familial dilated cardiomyopathy; Familial hypertrophic cardiomyopathy- 1; Familial hypertrophic cardiomyopathy-4; Heart block; Hypertrophic cardiomyopathy; Inborn genetic diseases; Left ventricular hypertrophy; Left ventricular noncompaction; Left ventricular noncompaction- 10; Long QT syndrome; MYBPC3 -related disorders; Noncompaction cardiomyopathy; Primary dilated cardiomyopathy; Primary familial hypertrophic cardiomyopathy; Tachycardia; Ventricular extrasystolesMYCN Inborn genetic diseasesMYEF2, SLC24A5 Oculocutaneous albinism type VI MYF5Abnormality of the ribs; External ophthalmoplegia with rib and vertebral anomalies; External ophthalmoplegia; ScoliosisMYH11,NDE1 Familial aortopathyMYH2, MYHAS Proximal myopathy and ophthalmoplegia MYH3Contractures, pterygia, and variable skeletal fusions syndrome 1A; Spondylocarpotarsal synostosis syndromeMYH6 Familial hypertrophic cardiomyopathy- 1MYH7 Hypertrophic cardiomyopathy; Primary dilated cardiomyopathy MYH7, MHRTCardiomyopathy; Cardiovascular phenotype; Hypertrophic cardiomyopathy; MYH7-related disordersMYL2, LOG 114827850 Familial hypertrophic cardiomyopathy- 10MYLK Visceral myopathy MYO15ACongenital sensorineural hearing impairment; Autosomal recessive deafness-3; Nonsyndromic hearing loss and deafness; Rare genetic deafnessMYO3A Autosomal recessive deafness-30MYO5B Congenital microvillous atrophy MY06Deafness; Autosomal dominant nonsyndromic hearing loss and deafness- 22; Rare genetic deafness MY07A MYO7A-related disorders; Rare genetic deafness; Retinal dystrophy;Retinitis pigmentosa; Usher syndrome type IB; Usher syndrome type 1; Autosomal dominant deafness-1 1; Autosomal recessive deafness-2MYOCD Congenital megabladder; Prune belly syndromeMYRF Cardiac-urogenital syndrome NADSYN1Vertebral, cardiac, renal and limb defects syndrome-3; Congenital NAD deficiency disorder 282 WO 2024/216206 PCT/US2024/024492 NAGLUCharcot-Marie-Tooth disease axonal type 2V; MPS-III-B mucopolysaccharidosis; Sanfilippo syndromeNALCN Infantile hypotonia with psychomotor retardation and characteristic facies- 1 NBASFever-associated acute infantile liver failure syndrome; Infantile liver failure syndrome-2 NBN Acute lymphoid leukemia; Aplastic anemia; Breast-ovarian cancer; Familial cancer of breast; Hereditary breast and ovarian cancer syndrome; Hereditary cancer-predisposing syndrome; Lissencephaly; Microcephaly with normal intelligence and immunodeficiency; Ovarian neoplasms NCF1, LOC106029312 Autosomal recessive cytochrome b-positive chronic granulomatous disease type 1; Chronic granulomatous disease due to deficiency of NCF-1;Autosomal recessive cytochrome b-positive chronic granulomatous disease type IIINCR1,NLRP7 Recurrent hydatidiform mole-1NCSTN Familial acne inversa-lNDE1 Lissencephaly-4NDNF Hypogonadotropic hypogonadism-25 with anosmiaNDUFA12 Leigh syndrome NDUFAF2 Inborn genetic diseases; Leigh syndrome; Nuclear type 10 mitochondrial complex I deficiency; Nuclear type 1 mitochondrial complex I deficiency; NDUFAF2-related disordersNDUFAF3 Mitochondrial complex I deficiencyNDUFB11 Linear skin defects with multiple congenital anomalies-3NDUFS4 Leigh syndrome; Nuclear type 1 mitochondrial complex I deficiencyNDUFS6 Nuclear type 9 mitochondrial complex I deficiency NDUFVINuclear type 4 mitochondrial complex I deficiency; Nuclear type mitochondrial complex I deficiency NEBInborn genetic diseases; Nemaline myopathy; Nemaline myopathy -2; Non- immune hydrops fetalisNEB, RIF1 Nemaline myopathy; Nemaline myopathy-2 NEBL Hypertrophic cardiomyopathy; Long QT syndrome; Primary dilated cardiomyopathy; Primary familial hypertrophic cardiomyopathy; Sudden unexplained deathNEFL Charcot-Marie-Tooth disease type 2E NEK1 Susceptibility to amyotrophic lateral sclerosis-24; Majewski type; Short rib- polydactyly syndrome; Short-rib thoracic dysplasia-3 with or without polydactylyNEURODI Maturity-onset diabetes of the young type 6NEXN Dilated cardiomyopathy-lCC; Familial hypertrophic cardiomyopathy-20 NF1 Axillary freckling; Cafe-au-lait macules with pulmonary stenosis; Focal Thyperintense basal ganglia lesion; Ganglioglioma; Hereditary cancer- predisposing syndrome; Inborn genetic diseases; Juvenile myelomonocytic leukemia; Multiple cafe-au-lait spots; Familial spinal neurofibroma;Neurofibromas; Neurofibromatosis type 1; Neurofibromatosis-Noonan 283 WO 2024/216206 PCT/US2024/024492 syndrome; Optic nerve glioma; Pilocytic astrocytoma; Tibial pseudoarthrosis NF1, LOC111811965 Hereditary cancer-predisposing syndrome; Neurofibromatosis type 1NF2 Meningioma; Neurofibromatosis type 2 NFIBAcquired macrocephaly with impaired intellectual development; Intellectual disability; Macrocephaly; MacrocephalusNFIX Marshall-Smith syndrome NGLYlCongenital disorder of deglycosylation; Intellectual disability; Neuromotor delay; Peripheral neuropathyNHLRC1 Lafora disease; Progressive myoclonic epilepsy-2NHLRC2 Fibrosis, neurodegeneration, and cerebral angiomatosisNHS Nance-Horan syndromeNIPAL4 Autosomal recessive congenital ichthyosis-6NIPBL Cornelia de Lange syndrome- 1 NKX2-5Abnormality of cardiovascular system morphology; Atrial septal defect-with or without atrioventricular conduction defectsNKX3-2 Spondylo-megaepiphyseal-metaphyseal dysplasiaNKX6-2 Autosomal recessive spastic ataxia-8 with hypomyelinating leukodystrophy NLGN4XSusceptibility to X-linked autism-2; Non-syndromic X-linked intellectual disabilityNLRP7 Recurrent hydatidiform mole-1NOTCH 1 Adams-Oliver syndrome-5; Aortic valve disorder; Congenital heart defectNPC1 Niemann-Pick disease type C; Niemann-Pick disease type ClNPHP1 Nephronophthi si s; Nephronophthi si s- 1NPHP3, NPHP3-AC AD 11 Meckel syndrome type 7NPHS1 Finnish congenital nephrotic syndrome NPHS2Idiopathic nephrotic syndrome; Idiopathic steroid-resistant nephrotic syndromeNPHS2,AXDND1Idiopathic nephrotic syndrome; Nephrotic range proteinuria; Idiopathic steroid-resistant nephrotic syndromeNPRL3, HBA- LCR Familial focal epilepsy with variable foci-3NROBI X-linked congenital adrenal hypoplasia NR2E3 Abnormality of color vision; Cone-rod dystrophy; Enhanced s-cone syndrome; Horizontal nystagmus; NR2E3-related disorders; Retinal dystrophy; Retinitis pigmentosa; Retinitis pigmentosa-37; Visual impairmentNR3C2 Autosomal dominant pseudohypoaldosteronism type 1 NSDIBeckwith-Wiedemann syndrome; Inborn genetic diseases; Sotos syndrome- 284 WO 2024/216206 PCT/US2024/024492 NSD2 4p partial monosomy syndrome; Wolf-Hirschhorn like syndromeNSMCE2 Seckel syndrome- 10NSMF Hypogonadotropic hypogonadism-9 with or without anosmiaNSUN2 Autosomal recessive mental retardation-5NT5E Calcification of joints and arteries NTHLIFamilial adenomatous polyposis-3; Hereditary cancer-predisposing syndromeNTRK1 Hereditary insensitivity to pain with anhidrosisOAT Ornithine aminotransferase deficiencyOBSL1 Three M syndrome-2 OCA2Variation in skin/hair/eye pigmentation- 1; Tyrosinase-positive oculocutaneous albinismOCLN Pseudo-TORCH syndrome- 1 OFDIJoubert syndrome; Orofaciodigital syndrome 1; Simpson-Golabi-Behmel syndrome type 2 OP AlAbortive cerebellar ataxia; Dominant hereditary optic atrophy; Inborn genetic diseases; Mitochondrial diseases; Retinal dystrophy OPHN1Mental retardation X-linked with cerebellar hypoplasia and distinctive facial appearanceOPNIEW Cone monochromatismORC6 Meier-Gorlin syndrome-3 OSGIN2, NBNHereditary cancer-predisposing syndrome; Microcephaly with normal intelligence and immunodeficiency OTCAbnormality of ornithine metabolism; Hyperammonemia; Ornithine carbamoyltransferase deficiency; Protein avoidanceOTOA Autosomal recessive deafness-22; Rare genetic deafnessOTOF Autosomal recessive deafness-9; Rare genetic deafness OTOGAutosomal recessive deafness-18B; Intellectual disability; Rare genetic deafness; SeizuresOTOGE Rare genetic deafness OTUD6B Dysmorphic features; Epilepsy; Intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies; Intellectual disabilityOTX2 Syndromic microphthalmia type 5P2RY12, MED12L Platelet-type bleeding disorder-8P3H1 Osteogenesis imperfecta type 8P3H2 High myopia with cataract and vitreoretinal degenerationP4HA2 Autosomal dominant myopia-25PAFAH1B1 Inborn genetic diseases; Lissencephaly due to LISI mutationPAH Phenylketonuria 285 WO 2024/216206 PCT/US2024/024492 PALB2 Basal cell carcinoma; Breast cancer; Cancer of the pancreas; Familial cancer of breast; Complementation group N Fanconi anemia; Generalized hypopigmentation; Hereditary breast and ovarian cancer syndrome; Hereditary cancer; Hereditary cancer-predisposing syndrome; Neoplasm of the breast; Ovarian neoplasms; PALB2-related disorders; Susceptibility to pancreatic cancer-3; Pre-B-cell acute lymphoblastic leukemia;Tracheoesophageal fistula; Tumor susceptibility linked to germline BAPmutationsPANK2 Pigmentary pallidal degenerationPAPSS2 Pakistani type spondyloepimetaphyseal dysplasiaPARN Autosomal recessive dyskeratosis congenita-6PATL2 Oocyte maturation defect-4PAX2 Focal segmental glomerulosclerosis-7; Renal coloboma syndrome PAX3Rare genetic deafness; Waardenburg syndrome; Waardenburg syndrome type 1PAX6 Aniridia-1; Autosomal dominant keratitisPAX9 Selective tooth agenesis-3PC Pyruvate carboxylase deficiencyPCCA Propionic acidemiaPCCB Propionic acidemia PCDH15 Deafness; Autosomal dominant nonsyndromic deafness-23; Rare genetic deafness; Retinal dystrophy; Digenic Usher syndrome type ID/F; Usher syndrome type 1G; Usher syndrome type 1; Usher syndrome type ID; Usher syndrome type IF PCDH19 Absence seizures; Delayed speech and language development; Early infantile epileptic encephalopathy -9; Frontal cortical atrophy; Generalized seizures; Generalized tonic-clonic seizures; Global developmental delay; Hand tremor; Long palpebral fissure; Prominent fingertip pads; Strabismus; Temporal cortical atrophyPCLO Pontocerebellar hypoplasia type 3PCNT Microcephalic osteodysplastic primordial dwarfism type 11PCSKI, LOC101929710 Proprotein convertase 1/3 deficiency PCSK9Familial hypercholesterolemia; Familial hypercholesterol emia-1; Low density lipoprotein cholesterol level quantitative trait locus 1PCYT1A Spondylometaphyseal dysplasia-cone-rod dystrophy syndromePDE11A Primary pigmented nodular adrenocortical disease-2PDE6B Retinal dystrophy; Retinitis pigmentosa; Retinitis pigmentosa-40PDE6C Achromatopsia- 5PDE8B Autosomal dominant striatal degeneration- 1PDHA1 Inborn genetic diseases; Pyruvate dehydrogenase El-alpha deficiency PDXIPermanent neonatal diabetes mellitus-1; Maturity-onset diabetes of the young type 4; Pancreatic agenesis- 1 286 WO 2024/216206 PCT/US2024/024492 PDZD7Autosomal recessive deafness-57; Rare genetic deafness; Usher syndrome type 2APEPD Prolidase deficiency PEX1 Deafness enamel hypoplasia nail defects; Zellwegar peroxisome biogenesis disorder-lA; Peroxisome biogenesis disorder-lB; Peroxisome biogenesis disorders; Retinal dystrophy; Zellweger syndrome spectrum PEX1, GAT ADI Deafness/enamel hypoplasia/nail defects; Zellweger peroxisome biogenesis disorder 1A; Peroxisome biogenesis disorder IB; Peroxisome biogenesis disorders; Zellweger syndrome spectrum PEX10 Complementation group 7 peroxisome biogenesis disorder; Peroxisome biogenesis disorder-6A; Peroxisome biogenesis disorder-6B; Peroxisome biogenesis disorders; Zellweger syndrome spectrumPEX10, PLCH2 Peroxisome biogenesis disorder-6B PEX12Infantile Refsum ’s disease; Peroxisome biogenesis disorder-3 A; Peroxisome biogenesis disorders; Zellweger syndrome spectrum PEX2 Peroxisome biogenesis disorder-5B; Zellweger peroxisome biogenesis disorder-5 A; Peroxisome biogenesis disorders; Zellweger syndrome spectrum PEX26Peroxisome biogenesis disorder-7A; Peroxisome biogenesis disorder-7B; Peroxisome biogenesis disorders; Zellweger syndrome spectrum PEX6 Heimler syndrome-2; Peroxisome biogenesis disorder-4B; Zellweger peroxisome biogenesis disorder-4A; Peroxisome biogenesis disorders; Retinal dystrophy; Zellweger syndrome spectrum PEX7PEX7-related disorders; Peroxisome biogenesis disorder-9B; Phytanic acid storage disease; Rhizomelic chondrodysplasia punctata type 1PGAM2, DBNL Glycogen storage disease type XPGAPI Autosomal recessive mental retardation-42PGAP3 Hyperphosphatasia with mental retardation syndrome-4PGM3, DOPIA Immunodefi ci ency-23PHEX Familial X-linked hypophosphatemic vitamin D refractory ricketsPHEX,PTCHD1-AS Familial X-linked hypophosphatemic vitamin D refractory ricketsPHF3, EYS Retinal dystrophy; Retinitis pigmentosa-25PHF6 Borjeson-Forssman-Lehmann syndromePHGDH Phosphoglycerate dehydrogenase deficiency PHIPDevelopmental delay, intellectual disability, obesity, and dysmorphic featuresPHYH Phytanic acid storage disease; Adult refsum disease- 1PI4KA Perisylvian polymicrogyria with cerebellar hypoplasia and arthrogryposisPIGA Paroxysmal nocturnal hemoglobinuria- 1PIGN Multiple congenital anomalies-hypotonia-seizures syndrome-1 PIGOHyperphosphatasia with mental retardation syndrome-2; Hyperphosphatasia-intellectual disability syndrome 287 WO 2024/216206 PCT/US2024/024492 PIGTMultiple congenital anomalies-hypotonia-seizures syndrome-3; PIGT- related disorderPIK3R1 SHORT syndromePINKI Autosomal recessive early-onset Parkinson disease-6PIRC66, MIR4713HG, CYP19A1 Aromatase deficiencyPITX3 Anterior segment mesenchymal dysgenesis; Cataract- 11PJVK Autosomal recessive deafness-59; Rare genetic deafness PKDIAutosomal recessive polycystic kidney disease; Adult type polycystic kidney diseasePKD1, LOC105371049 Adult type polycystic kidney disease PKHDIAutosomal recessive polycystic kidney disease; Polycystic kidney dysplasia; Polycystic liver diseasePKP1 Epidermolysis bullosa simplex due to plakophilin deficiency PKP2 Arrhythmogenic right ventricular cardiomyopathy; Arrhythmogenic right ventricular dysplasia/cardiomyopathy; Arrhythmogenic ventricular cardiomyopathy type 9; Cardiac arrhythmia; Cardiomyopathy;Cardiovascular phenotype; Sudden unexplained deathPLA2G5 Familial benign fleck retina PLA2G6 Infantile neuroaxonal dystrophy; Iron accumulation in brain;Neurodegeneration with brain iron accumulation-2B; PLA2G6-associated neurodegenerationPLCBI Early infantile epileptic encephalopathy- 12PLCB4 Auriculocondylar syndrome-2PLCDI Leukonychia totalisPLDI Developmental cardiac valvular defectPLD3, PRX Charcot-Marie-Tooth disease; Spinocerebellar ataxia-46PLEC Epidermolysis bullosa simplex with muscular dystrophy PEN, CEP85L Cardiac arrest; Cardiomyopathy; Cardiovascular phenotype; Dilated cardiomyopathy-IP; Familial hypertrophic cardiomyopathy- 18;Hypertrophic cardiomyopathy; Primary dilated cardiomyopathy; Sudden cardiac death PLODICardiovascular phenotype; Hydroxylysine-deficient Ehlers-Danlos syndromePLOD2 Bruck syndrome-2PLP1, RAB9B Hereditary spastic paraplegia-2PLS3 Bone mineral density quantitative trait locus 18PMFBP1 Spermatogenic failure-3 1PMM2 Congenital disorder of glycosylation type IAPMP22 Charcot-Marie-Tooth disease 288 WO 2024/216206 PCT/US2024/024492 PMS2 Acute lymphoid leukemia; Burkitt lymphoma; Colorectal cancer; Glioblastoma; Hereditary cancer; Hereditary cancer-predisposing syndrome; Hereditary nonpolyposis colon cancer; Hereditary nonpolyposis colorectal cancer type 4; Lymphoma; Lynch syndrome; Lynch syndrome-I; Pulmonary arterial hypertension; Pulmonary insufficiency; Respiratory insufficiency; Tumor susceptibility linked to germline BAP1 mutations; Turcot syndromePNKD, CATIP-AS2 Paroxysmal nonkinesi genic dyskinesia- 1 PNKP Ataxia-oculomotor apraxia-4; Early infantile epileptic encephalopathy- 10; Early infantile epileptic encephalopathy- 12; History of neurodevelopmental disorderPNPLA2 Neutral lipid storage myopathy PNPLA6 Hereditary spastic paraplegia-39; Laurence-Moon syndrome; PNPLA6- related disorders; Trichomegaly-retina pigmentary degeneration-dwarfism syndromePNPLA8 Mitochondrial myopathy-lactic acidosis-deafness syndromePNPO Pyridoxal phosphate-responsive seizuresPOC5 Retinitis pigmentosa; Syndromic retinitis pigmentosaPOGLUTI Dowling-degos disease-4 POGZGlobal developmental delay; Speech apraxia; White-sutton syndrome; Dysmorphy; Intellectual deficiency POLAIVan Esch-O ’Driscoll syndrome; Van Esch type X-linked intellectual disability POLDI Colorectal cancer- 10; Hereditary cancer-predisposing syndrome;Mandibular hypoplasia, deafness, progeroid features and lipodystrophy syndrome POLE Susceptibility to colorectal cancer- 12; Hereditary cancer-predisposing syndrome; Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency POLGGeneralized epilepsy; Global developmental delay; Obesity; Progressive sclerosing poliodystrophy; SeizuresPOLH Variant type xeroderma pigmentosumPOLRIA Cincinnati type acrofacial dysostosisPOLRIC Treacher Collins syndrome-3POLRID Treacher Collins syndrome-2POLR2F, SOX10 Rare genetic deafness; Waardenburg syndrome type 4C POLR3AHypomyelinating leukodystrophy-7; Neonatal pseudo-hydrocephalic progeroid syndrome POLR3B Cerebellar hypoplasia with endosteal sclerosis; Hypogonadotropic hypogonadism-7 with or without anosmia; Hypomyelinating leukodystrophy-7; Hypomyelinating leukodystrophy-8 with or without oligodontia and/or hypogonadotropic hypogonadismPOMK Limb-girdle muscular dystrophy-dystroglycanopathy type C-12 289 WO 2024/216206 PCT/US2024/024492 POMTI Congenital muscular dystrophy-dystroglycanopathy with mental retardation type Bl; Limb-girdle muscular dystrophy-dystroglycanopathy type Cl;Congenital muscular dystrophy-dystroglycanopathy type Al with brain and eye anomalies; POMTI-related disorders; Walker-Warburg congenital muscular dystrophy POMT2 Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A2; Limb-girdle muscular dystrophy-dystroglycanopathy type C2POP1 Anauxetic dysplasia-2 POR Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis; Disordered steroidogenesis due to cytochrome p4oxidoreductase deficiencyPORCN Focal dermal hypoplasia POTIHereditary cancer-predisposing syndrome; Susceptibility to cutaneous malignant melanoma- 10POU3F4 X-linked deafness-2; Rare genetic deafnessPOU4F3 Rare genetic deafness PPARGType II diabetes mellitus; Digenic noninsulin-dependent diabetes mellitus with acanthosis nigricans and hypertensionPPIB Osteogenesis imperfecta type 9PPOX Variegate porphyriaPPP1R12A Genitourinary and/or brain malformation syndrome PPTIHistory of neurodevelopmental disorder; Neuronal ceroid-lipofuscinosis;Recessive neuronal ceroid lipofuscinosis; Neuronal ceroid lipofuscinosis-1 PQBP1Delayed speech and language development; Hyperactivity; Inborn genetic diseases; Intellectual disability; Microcephaly; Renpenning syndrome-1PRDM16 Left ventricular noncompaction-8PRDM5 Brittle cornea syndrome-2PRDX1, MMACHC Digenic cblC type methylmalonic aciduria and homocystinuria PRF1Familial hemophagocytic lymphohistiocytosis; Familial hemophagocytic lymphohi stiocytosi s-2PRKARIA Carney complex type 1PRKARIA, FAM20A Amelogenesis imperfecta type 1GPRKAR1B,DNAAF5 Primary ciliary dyskinesia-18PRKCSH Polycystic liver disease- 1PRKN Parkinson disease-2 PRMT7Short stature, brachydactyly, intellectual developmental disability, and seizuresPROK2 Hypogonadotropic hypogonadism-4 with or without anosmiaPROKR2 Inborn genetic diseases; Kallmann syndrome-3 290 WO 2024/216206 PCT/US2024/024492 PROMICone-rod dystrophy-12; PROMl-related disorders; Retinal dystrophy;Retinitis pigmentosa; Retinitis pigmentosa-41PROPI Combined pituitary hormone deficiency-2 PRPH2Adult-onset vitelliform macular dystrophy; Retinal dystrophy; Retinitis pigmentosa-7; Retinitis punctata albescens PRRT2 Episodic kinesigenic dyskinesia-1; History of neurodevelopmental disorder; Infantile convulsions and choreoathetosis; Paroxysmal kinesigenic dyskinesia; Paroxysmal nonkinesigenic dyskinesia-1; Benign familial infantile seizures-2PRSS12 Autosomal recessive mental retardation- 1PRSS56 Isolated microphthalmia-6PRX Demyelinating Charcot-Marie-Tooth disease type 4FPSAP Combined saposin deficiencyPSENI Familial acne inversa-3PSENEN Familial acne inversa-2PTCHI Gorlin syndrome; Hereditary cancer-predisposing syndromePTCH2 Gorlin syndrome; Medulloblastoma PTEN Cowden syndrome; Cowden syndrome-1; Glioblastoma; Glioma susceptibility-2; Hemangioma; Hereditary cancer-predisposing syndrome; inborn genetic diseases; Macrocephaly/autism syndrome; Malignant tumor of prostate; Familial meningioma; Neoplasm of brain; Neoplasm of the breast; Neoplasm of the large intestine; Non-small cell lung cancer; Ovarian neoplasms; PTEN hamartoma tumor syndrome; PTEN-related disorder; Proteus-like syndrome; VACTERL association with hydrocephalusPTHIR Blomstrand type chondrodysplasiaPTPN11 Metachondromatosi sPTPRF Aplasia or hypoplasia of breasts and/or nipples-2PTPRO Nephrotic syndrome type 6 PTSBH4-def1cient hyperphenylalaninemia-A; BH4-def1cient hyperphenylalaninemia due to partial PTS deficiencyPUF60 Verheij syndrome PURA Apnea; Generalized hypotonia; Autosomal dominant intellectual disability- 31; Limb dystonia; Mental retardation; PURA Syndrome; PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome due to a point mutation PUS7Intellectual developmental disorder with abnormal behavior, microcephaly, and short staturePXDN Anterior segment dysgenesis-7PYCRI Autosomal recessive cutis laxa type 2BPYGL Glycogen storage disease type VIPYGM Glycogen storage disease type VRAB23 Carpenter syndrome; Carpenter syndrome- 1RAB27A Griscelli syndrome; Griscelli syndrome type 2RAB33B Smith-McCort dysplasia-2 291 WO 2024/216206 PCT/US2024/024492 RAB3GAP1 Warburg micro syndrome- 1RABL3 Susceptibility to pancreatic cancer- 5 RAD50Hereditary cancer-predisposing syndrome; Nijmegen breakage syndrome- like disorder RAD51C Familial breast-ovarian cancer-3; Complementation group O Fanconi anemia; Hereditary breast and ovarian cancer syndrome; Hereditary cancer- predisposing syndrome; Ovarian neoplasms; RAD51C-related disordersRAD51D, RAD51L3-RFFLFamilial breast-ovarian cancer-4; Hereditary breast and ovarian cancer syndrome; Hereditary cancer-predisposing syndrome; Ovarian neoplasmsRAD51L3-RFFL, RAD51D Familial breast-ovarian cancer-4; Hereditary cancer-predisposing syndromeRAIl Smith-Magenis syndrome RAPSNCongenital myasthenic syndrome- 11 associated with acetylcholine receptor deficiencyRARSI Hypomyelinating leukodystrophy-9 RASA1Capillary malformation-arteriovenous malformation; Capillary malformation-arteriovenous malformation- 1 RBIHereditary cancer-predisposing syndrome; Neoplasm; Osteosarcoma;Trilateral retinoblastoma; Small cell lung cancer; Urinary bladder cancerRBBP8 Microcephaly with mental retardation and digital anomalies RBM20Cardiovascular phenotype; Dilated cardiomyopathy-IDD; Primary dilated cardiomyopathyRBP3 Retinitis pigmentosa-66RD3 Leber congenital amaurosis- 12RDH12 Retinitis pigmentosa-53RDH5, BLOC1S1-RDH5 Fundus albipunctatus; Pigmentary retinal dystrophyRECQL Hereditary cancer-predisposing syndromeRECQL, PYROXDI Hereditary cancer-predisposing syndrome RECQL4 B lymphoblastic leukemia with t(12;21)(pl3;q22); Baller-Gerold syndrome; High grade surface osteosarcoma; Rapadilino syndrome; Rothmund- Thomson syndrome; Rothmund-Thomson syndrome type 2REEP6 Retinitis pigmentosa-77RELT Amelogenesis imperfecta type IIICREN Familial hyperproreninemiaRET Hirschsprung disease- 1; Sensorineural hearing lossRFX5 Complementation group C bare lymphocyte syndrome type 11RFXANK Complementation group B bare lymphocyte syndrome type 11 RFXAPComplementation group D bare lymphocyte syndrome type II; Bare lymphocyte syndrome-2RHAG Regulatory type Rh-null diseaseRI ICE Amorph type Rh-null disease 292 WO 2024/216206 PCT/US2024/024492 RHO Autosomal dominant retinitis pigmentosaRIF1,NEB Nemaline myopathy; Nemaline myopathy-2RIN2 Macrocephaly, alopecia, cutis laxa, and scoliosisRIPK1 Immunodeficiency -57 with autoinflammationRIPK4 Bartsocas-Papas syndromeRNASEH2A Aicardi Goutieres syndrome-4RNASEH2B Aicardi Goutieres syndrome-2RNF113A Nonphotosensitive trichothiodystrophy-5RNF216 Gordon Holmes syndromeROBO3 Familial horizontal gaze palsy with progressive scoliosis-1RORA, RORA- ASIIntellectual developmental disorder with or without epilepsy or cerebellar ataxiaRP1 Retinal dystrophy; Retinitis pigmentosa; Retinitis pigmentosa- 1RP1L1 Retinitis pigmentosa-88 RPE65 Leber congenital amaurosis-2; Retinitis pigmentosa-87 with choroidal involvement; RPE65-related disorders; Retinal dystrophy; Retinitis pigmentosa-20 RPGRInborn genetic diseases; Retinal dystrophy; X-linked retinitis pigmentosa and sinorespiratory infections with deafness; Retinitis pigmentosa- 15RPGRIP1 Leber congenital amaurosis-6RPGRIPIL Joubert syndrome; Joubert syndrome-7RPL36A-HNRNPH2, GLA Fabry diseaseRPL5, DIPK1A Diamond-Blackfan anemia; Diamond-Blackfan anemia- 1RPS10, RPS10- NUDT3 Diamond-Blackfan anemia-9RPS27 Diamond-Blackfan anemia- 17RPS6KA3 Coffin-Lowry syndrome; X-linked mental retardation- 19 RSPH1Kartagener syndrome; Primary ciliary dyskinesia; Primary ciliary dyskinesia-24 RSPH4APrimary ciliary dyskinesia-11; Kartagener syndrome; Primary ciliary dyskinesiaRSP02 Tetraamelia syndrome-2 RIEL 1, REEL 1-TNFRSF6B Autosomal recessive dyskeratosis congenita-5; Chronic form idiopathic fibrosing alveolitis; Telomere-related pulmonary fibrosis and/or bone marrow failure-3; Autosomal dominant dyskeratosis congenita-4RTN2 Hereditary spastic paraplegia-12 RTTNCongenital microcephaly; Microcephaly, short stature, and polymicrogyria with or without seizures RUNXIAcute myeloid leukemia; Familial platelet disorder with associated myeloid malignancy 293 WO 2024/216206 PCT/US2024/024492 RYRI Central core myopathy; Susceptibility to malignant hyperthermia- 1;Mini core myopathy; Multi-minicore disease and atypical periodic paralysis; Neuromuscular disease; RYRI-related disorders SACSAutosomal recessive spastic ataxia; Charlevoix-Saguenay spastic ataxia; Spastic paraplegiaSAG Oguchi ’s disease; Retinitis pigmentosa-47; SAG-related disordersSALLI Townes syndromeSAMD9L Ataxia-pancytopenia syndromeSAMHDI Aicardi Goutieres syndrome-5SASHI Dyschromatosis universalis hereditarian-1SATB2 SATB2-related disorderSBDS Inborn genetic diseases; Shwachman-Diamond syndrome- 1SBF1 Charcot-Marie-Tooth disease type 4 SCAPERAttention deficit hyperactivity disorder; Intellectual developmental disorder and retinitis pigmentosa; Intellectual disability; Rod-cone dystrophySCARB2 Progressive myoclonic epilepsy-4 with or without renal failureSCARF2 Van den Ende-Gupta syndrome SCNIA Autosomal dominant epilepsy; Early infantile epileptic encephalopathy; Familial hemiplegic migraine type 3; Generalized epilepsy with febrile seizures plus type 2; History of neurodevelopmental disorder; Severe myoclonic epilepsy in infancy; Dravet syndrome SCNIA, LOCI 0272405 8 Autosomal dominant epilepsy; Early infantile epileptic encephalopathy; Epileptic encephalopathy; Generalized epilepsy with febrile seizures plus type 2; Seizures; Severe myoclonic epilepsy in infancySCN2A SCN2A-related disorder SCN5A Brugada syndrome; Brugada syndrome with shorter-than-normal QT interval; Brugada syndrome- 1; Cardiovascular phenotype; Dilated cardiomyopathy-lE; Nonprogressive heart block; Long QT syndrome-1SCN5A, LOC110121269Brugada syndrome; Brugada syndrome with shorter-than-normal QT interval SCN9A, SCNIA-ASI Generalized epilepsy with febrile seizures plus type 7; Hereditary sensory and autonomic neuropathy type IIA; Autosomal recessive congenital indifference to pain SCNNIAAutosomal recessive pseudohypoaldosteronism type 1; Idiopathic bronchiectasisSCNNIB Liddle syndrome- 1SCNNIG Autosomal recessive pseudohypoaldosteronism type 1; Liddle syndrome-2SCO1 Mitochondrial complex IV deficiencySCP2 Leukoencephalopathy with dystonia and motor neuropathy SDCCAG8Bardet-Biedl syndrome; Bardet-Biedl syndrome- 16; Senior-Loken syndrome-7 SDHA Carney triad; Dilated cardiomyopathy-1GG; Hereditary cancer-predisposing syndrome; Leigh syndrome; Mitochondrial complex II deficiency;Paragangliomas-5; Pilocytic astrocytomaSDHAF2 Hereditary paraganglioma-pheochromocytoma syndromes 294 WO 2024/216206 PCT/US2024/024492 SDHB Carney-Stratakis syndrome; Gastrointestinal stromal tumor; Hereditary paraganglioma-pheochromocytoma syndromes; Hereditary cancer- predisposing syndrome; Paragangliomas-4; Pheochromocytoma SDHC Gastrointestinal stromal tumor; Hereditary paraganglioma- pheochromocytoma syndromes; Hereditary cancer-predisposing syndrome;Paragangliomas-3 SDHD Carney-Stratakis syndrome; Cowden syndrome-3; Hereditary paraganglioma-pheochromocytoma syndromes; Hereditary cancer- predisposing syndrome; Paragangliomas- 1; Paragangliomas- 1 with sensorineural hearing loss; PheochromocytomaSDR9C7 Autosomal recessive congenital ichthyosis-13SEC23B Congenital dyserythropoietic anemiaSEC24D Cole-Carpenter syndrome-2SECISBP2 Anormal thyroid hormone metabolism SELENBP1Extraoral halitosis due to methanethiol oxidase deficiency; Extraoral halitosisSELENON Eichsfeld type congenital muscular dystrophySEMA3A Hypogonadotropic hypogonadism- 16 with or without anosmiaSEPSECS Pontocerebellar hypoplasia type 2DSEPTIN 12 Spermatogenic failure- 10 SERAC13-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome; Mitochondrial oxidative phosphorylation disorderSERPINA6 Corticosteroid-binding globulin deficiencySERPINA7 Thyroxine-binding globulin quantitative trait locusSERPINB6 Rare genetic deafnessSERPINB7 Nagashima type palmoplantar keratodermaSERP INCI Antithrombin III deficiencySERPINF1 Osteogenesis imperfecta type VISERPINGI Hereditary angioedema type 1SERPINH1 Osteogenesis imperfecta type 10SETBP1 SETBP 1-related disorderSETD5 Inborn genetic diseases; Autosomal dominant mental retardation-23 SF3B4Hereditary hearing loss and deafness; Inborn genetic diseases; Nager syndromeSFRP4 Pyle metaphyseal dysplasiaSFTPAl Respiratory distress associated with prematuritySFTPB Pulmonary surfactant metabolism dysfunction-1SGCA Autosomal recessive limb-girdle muscular dystrophy type 2DSGCD Neuromuscular diseaseSGCE, CASD1 Myoclonic dystonia SGCGNorth African type severe autosomal recessive muscular dystrophy of childhood 295 WO 2024/216206 PCT/US2024/024492 SGSH Developmental regression; Diarrhea; Gastrointestinal dysmotility; Global developmental delay; MPS-III-A mucopolysaccharidosis; Nystagmus; Retinal dystrophy; Sanfilippo syndrome; Severe visual impairment SH2D1AX-linked lymphoproliferative syndrome-1; X-Linked Lymphoproliferative SyndromeSH3PXD2B Frank-Ter Haar syndrome SH3TC2 Charcot-Marie-Tooth disease type 4C; Charcot-Marie-Tooth disease type 4;Inborn genetic diseases; Mild mononeuropathy of the median nerve; SH3TC2-related disorders SHANK3 22ql3.3 deletion syndrome; Autism spectrum disorder; History of neurodevelopmental disorder; Inborn genetic diseases; SHANK3-related disorderSHOX Leri-Weill dyschondrosteosisSI Sucrase-isomaltase deficiencyS1X6 Colobomatous optic disc-macular atrophy-chorioretinopathy syndromeSKIV2L Trichohepatoenteric syndrome-2SLC10A7 Amelogenesis imperfecta, short stature, and skeletal dysplasia with scoliosisSLC12A1 Antenatal Bartter syndrome type 1SLC12A3 Familial hypokalemia-hypomagnesemia SLC12A6Agenesis of the corpus callosum with peripheral neuropathy; Charcot- Marie-Tooth diseaseSLC17A5 Salla disease; Severe infantile type sialic acid storage diseaseSLC19A1, COL18A1 Knobloch syndrome- 1 SLC19A2Thiamine-responsive megaloblastic anemia with diabetes mellitus and sensorineural deafnessSLC19A3 Biotin-responsive basal ganglia diseaseSLC22A5 Renal carnitine transport defectSLC25A20 Carnitine acylcarnitine translocase deficiency SLC26A2 3MC syndrome-2; Achondrogenesis type IB; Atelosteogenesis type II;Diastrophic dysplasia; Multiple epiphyseal dysplasia type 4; Osteochondrodysplasia; SLC26A2-related disordersSLC26A3 Congenital chloride type secretory diarrheaSLC26A4 Enlarged vestibular aqueduct; Pendred syndrome; Rare genetic deafnessSLC2A10 Arterial tortuosity syndrome; Cardiovascular phenotypeSLC2A2 Fanconi-Bickel syndromeSLC30A8 Diabetes mellitus type 2SLC33A1 Autosomal dominant spastic paraplegia; Spastic paraplegia-42SLC34A3 Autosomal recessive hypophosphatemic bone diseaseSLC35A2 Congenital disorder of glycosylation type IIMSLC35D1 Schneckenbecken dysplasia SLC37A4Glucose-6-phosphate transport defect; Glycogen storage disease; Inborn genetic diseases; Phosphate transport defect 296 WO 2024/216206 PCT/US2024/024492 SLC38A8Foveal hypoplasia-2 with optic nerve misrouting and anterior segment dysgenesisSLC39A4 Hereditary acrodermatitis enteropathicaSLC45A2 Oculocutaneous albinism type 4SLC4A1 Autosomal dominant distal renal tubular acidosisSLC4A11 Corneal endothelial dystrophy; Fuchs endothelial corneal dystrophy-4SLC52A3 Brown-Vialetto-Van Laere syndrome- 1SLC6A1 Myoclonic-atonic epilepsy; SLC6A1-related disorderSLC9A3 Congenital secretory sodium diarrhea-8SLC9A3, SLC9A3-AS1 Congenital secretory sodium diarrhea-8 SLC9A6Gastrostomy tube feeding in infancy; Global developmental delay;Recurrent respiratory infections; Scoliosis; Seizures; Sleep disturbanceSLCO2A1 Autosomal recessive primary hypertrophic osteoarthropathy-2SLITRK1 Tourette Syndrome; TrichotillomaniaSLURP 1 AcroerythrokeratodermaSMAD3 Familial thoracic aortic aneurysm and aortic dissection SMAD4 Carcinoma of pancreas; Hereditary cancer-predisposing syndrome; Juvenile polyposis syndrome; Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome; Myhre syndrome SMAD6Aortic valve disease-2; Aortic valve disorder; Susceptibility to craniosynostosis-7SMARCA4 NeuroblastomaSMARCALl Schimke immuno-osseous dysplasiaSMARCBI Atypical teratoid tumorSMARCEl Familial meningioma SMCIACongenital muscular hypertrophy-cerebral syndrome; Early infantile epileptic encephalopathy-85 with or without midline brain defectsSMN1 Werdnig-Hoffmann disease SMPD1Niemann-Pick disease type A; Niemann-Pick disease type B; Sphingomyelin/cholesterol lipidosisSNAP29 CEDNIK syndrome; Hypomyelinating leukodystrophy-2SNRPB Cerebro-costo-mandibular syndromeSOHLHI Nonsyndromic hypergonadotropic hypogonadism; Ovarian dysgenesis-5SON inborn genetic diseases; ZTTK syndromeSOS1 Gingival fibromatosis- 1SOX2, SOX2- OT Anophthalmia/microphthalmia-esophageal atresia syndromeSOX9 Campomelic dysplasia with autosomal sex reversal; Camptomelic dysplasiaSOX9, LOCI 08021846 Campomelic dysplasia with autosomal sex reversalSP110, SP140 Hepatic veno-occlusive disease-immunodeficiency syndromeSP7 Osteogenesis imperfecta type 12SPART Troyer syndrome 297 WO 2024/216206 PCT/US2024/024492 SPAST Autosomal dominant spastic paraplegia-4SPEF2 Primary ciliary dyskinesia; Spermatogenic failure-43SPEC Centronuclear myopathy-5SPEG, ASIC4- ASI Centronuclear myopathy-5 SPG11Amyotrophic lateral sclerosis type 5; Autosomal recessive hereditary spastic paraplegia; Spastic parapl egi a- 11 SPG7Hereditary spastic paraplegia; Hereditary spastic paraplegia-7;Mitochondrial diseasesSPINK2 Spermatogenic failure-29SPINK5 Netherton syndromeSPNS2 Autosomal recessive deafness-1 15; Inborn genetic diseasesSPRTN Ruijs-Aalfs syndromeSPTAl Elliptocytosis-2; Hereditary pyropoikilocytosisSPTB Hereditary spherocytosis; Spherocytosis type 2 SQSTMlAmyotrophic lateral sclerosis and/or frontotemporal dementia-1; Early- onset Paget disease of bone-2; SQSTMl-related disorderSRCAP Floating-Harbor syndromeSRY 46,XY sex reversal type 1STU Autosomal recessive congenital ichthyosis-11STAGI Autosomal dominant mental retardation-47 STAG3Abnormality of the ovary; Female infertility; Premature ovarian failure-8; Premature ovarian insufficiencySTATI Autosomal recessive susceptibility to mycobacterial and viral infections STIM1Combined immunodeficiency due to STIM1 deficiency; Tubular aggregate myopathy- 1; Stormorken syndromeSTK11 Hereditary cancer-predisposing syndrome; Peutz-Jeghers syndromeSTRA6 Microphthalmia syndromic-9STRC Autosomal recessive deafness-16; Rare genetic deafness STXBP1Early infantile epileptic encephalopathy; Early infantile epileptic encephalopathy-4; Epileptic encephalopathySTXBP2 Familial hemophagocytic lymphohistiocytosis-5 SUCLGIEncephalomyopathic mitochondrial DNA depletion syndrome-9 with methylmalonic aciduria SUFUGorlin syndrome; Desmoplastic medulloblastoma; Medulloblastoma with extensive nodularity SULT2B1Autosomal recessive congenital ichthyosis-14; Autosomal recessive congenital ichthyosis-2SUMF1 Multiple sulfatase deficiencySUNS Spermatogenic failure-16 SURF1 Abnormal pyramidal signs; Cerebellar ataxia; Charcot-Marie-Tooth disease type 4K; Dysarthria; Inborn genetic diseases; Leigh syndrome; Leigh syndrome due to COX IV deficiency; Leigh syndrome due to mitochondrial 298 WO 2024/216206 PCT/US2024/024492 complex IV deficiency; Mitochondrial complex IV deficiency; Muscle weakness SUZI 2 Imagawa-Matsumoto syndrome SYCP2Cryptozoospermia; Early spermatogenesis maturation arrest; Oligosynaptic infertilitySYCP3 Spermatogenic failure-4 SYNEl Myogenic type arthrogryposis multiplex congenita; Cerebellar ataxia;Autosomal dominant Emery-Dreifuss muscular dystrophy-4; Autosomal recessive spinocerebellar ataxia-8SYNE4 Rare genetic deafnessSYNGAPI Inborn genetic diseases; Autosomal dominant mental retardation-5SZT2 Early infantile epileptic encephalopathy- 18TAC3 Hypogonadotropic hypogonadism- 10 with or without anosmiaTACOl Mitochondrial complex IV deficiencyTALDOl Deficiency of transaldolase TANGO2 Acute rhabdomyolysis; Cardiac arrhythmia; Episodic flaccid weakness;Intellectual functioning disability; Seizures; Recurrent metabolic crises with rhabdomyolysis, cardiac arrhythmias, and neurodegenerationTAPI Bare lymphocyte syndrome type 1TAP2 Bare lymphocyte syndrome type 1; Peptide transporter PSF2 polymorphismTAZ 3-Methylglutaconic aciduria type 2TBC1D20 Warburg micro syndrome-4 TBC1D24 DOORS syndrome caused by mutation in the TBC1 domain family member 24; Early infantile epileptic encephalopathy-1; Inborn genetic diseases;Autosomal dominant deafness-65 TBCKInborn genetic diseases; Syndromic infantile encephalopathy; Infantile hypotonia with psychomotor retardation and characteristic facies-3 TBR1 Susceptibility to autism-5; Autistic behavior; Intellectual disability;Moderate global developmental delay; Neurodevelopmental disorder; Severe global developmental delayTBX19 Adrenocorticotropic hormone deficiencyTBX22 Cleft palate with ankyloglossiaTBX3 Ulnar-mammary syndromeTBX4 Coxopodopatellar syndromeTBX5 Variable congenital heart disease; Holt-Oram syndromeTBXASI Ghosal hematodiaphyseal dysplasia; Thromboxane synthetase deficiency TCAPAutosomal recessive limb-girdle muscular dystrophy type 2G; Dilated cardiomyopathy-lN; Primary familial hypertrophic cardiomyopathyTCP 12 Craniosynostosis-3TCF20 Neurodevelopmental abnormalityTCF4 Intellectual disability; Pitt-Hopkins syndromeTCN2 Inborn genetic diseases; Transcobalamin II deficiencyTCOFI Treacher Collins syndrome- 1 299 WO 2024/216206 PCT/US2024/024492 TCTEX1D2 Short-rib thoracic dysplasia- 17 with or without polydactylyTCTEX1D2, TM4SF19- TCTEX1D2 Short-rib thoracic dysplasia-17 with or without polydactylyTCTN2 Joubert syndrome; Meckel syndrome type 8TCTN3 Orofacial-digital syndrome-IVTD02 Familial hypertryptophanemiaTDRD7 Autosomal recessive congenital cataract-4TDRD9 Spermatogenic failure-30TECPR2 Autosomal recessive spastic paraplegia-49 TECTA Autosomal dominant nonsyndromic hearing loss and deafness- 12; Rare genetic deafness; Autosomal recessive deafness-21; Neurosensory autosomal recessive deafness-21TENM3 Syndromic microphthalmia- 15TENT5A Osteogenesis imperfecta type 18TEX 14 Spermatogenic failure-23TEX 15 Spermatogenic failure-25TFAP2B Patent ductus arteriosus-2TFR2 Hemochromatosis type 3TG lodotyrosyl coupling defectTGFB2 Cardiovascular phenotype; Holt-Oram syndrome; Loeys-Dietz syndrome-4TGFB3 Cardiovascular phenotype; Loeys-Dietz syndrome-5TGFBRI Familial thoracic aortic aneurysm and aortic dissection TGFBR2 Familial thoracic aortic aneurysm and aortic dissection; Hereditary nonpolyposis colorectal cancer type 6; Loeys-Dietz syndrome; Loeys-Dietz syndrome-2; Malignant tumor of esophagusTGM1 Autosomal recessive congenital ichthyosis-1; IchthyosisTGM5 Peeling skin syndrome-2TH Autosomal recessive Segawa syndromeTHRB Autosomal dominant generalized thyroid hormone resistanceTIC AMI Susceptibility to herpes simplex encephalitis-4TIMM8A Deafness dystonia syndromeTIMMDC1 Leigh syndromeTJP2 Progressive familial intrahepatic cholestasis-4TK2 Mitochondrial DNA depletion syndrome-2 TLR5Legionellosis; Melioidosis; Susceptibility to systemic lupus erythematosus- TM4SF20 Specific language impairment- 5TMCI Rare genetic deafness; Autosomal recessive nonsyndromic hearing loss-7 TMCOlCraniofacial dysmorphism, skeletal anomalies, and mental retardation syndromeTMCO6, NDUFA2 Cystic leukoencephalopathy 300 WO 2024/216206 PCT/US2024/024492 TMEM127Hereditary paraganglioma-pheochromocytoma syndromes; Hereditary cancer-predisposing syndrome; Pheochromocytoma TMEM216Joubert syndrome; Joubert syndrome-2; Meckel syndrome type 2;TMEM216-related disordersTMEM237 Joubert syndromeTMEM260 Structural heart defects and renal anomalies syndrome TMEM67 Cerebellar vermis hypoplasia; Generalized hypotonia; Iris coloboma;Joubert syndrome; Joubert syndrome-6; Meckel syndrome type 3; Meckel- Gruber syndrome; Nystagmus; TMEM67-related disorders TMEM70Mitochondrial proton-transporting ATP synthase complex deficiency;Nuclearly-encoded mitochondrial complex V (ATP synthase) deficiency-2 TMEM94Intellectual developmental disorder with cardiac defects and dysmorphic faciesTMEM99, KRT10 Bullous ichthyosiform erythroderma TMPRSS3Inborn genetic diseases; Rare genetic deafness; Autosomal recessive deafness-8TNFRSF1OB Squamous cell carcinoma of the head and neckTNFRSF11B Hyperphosphatasemia with bone disease TNFRSF13B Absent epiphyses; Chronic lung disease; Cleft palate; Clubfoot; Coat hanger sign of ribs; Common variable immune deficiency; Common variable immunodeficiency-2; Hemivertebrae; Immunoglobulin A deficiency -2; Interstitial pulmonary abnormality; Micrognathia; Patent ductus arteriosus; Preaxial foot polydactyly; Pseudoarthrosis; Respiratory failure; Short femur; Skeletal dysplasia; Vertebral hypoplasia; Vertebral segmentation defectTNFRSFIA Familial Periodic Fever; Susceptibility to multiple sclerosis-5TNFSF11 Autosomal recessive osteopetrosis-2TNNI3 Cardiovascular phenotypeTNNI3K, FPGT-TNNI3K Cardiac conduction disease with or without dilated cardiomyopathy TNNT2 Cardiomyopathy; Cardiovascular phenotype; Familial hypertrophic cardiomyopathy -2; Familial restrictive cardiomyopathy-3; Hypertrophic cardiomyopathy; Left ventricular noncompaction-6; Primary familial hypertrophic cardiomyopathyTNPO3 Limb-girdle muscular dystrophy type IF TNXBClassic-like Ehlers-Danlos syndrome- 1; Ehlers-Danlos syndrome due to tenascin-X deficiencyTONSL Sponastrime dysplasiaTONSL, TONSL-ASI Sponastrime dysplasia TOP3AMicrocephaly, growth restriction, and increased sister chromatid exchange- TOPORS Retinal dystrophy; Retinitis pigmentosa 301 WO 2024/216206 PCT/US2024/024492 TPS 3 Head and neck neoplasms; Hereditary cancer-predisposing syndrome; Li- Fraumeni syndrome; Li-Fraumeni syndrome- 1; Li-Fraumeni-like syndrome; Multiple myeloma; Neoplasm of the large intestine; Ovarian neoplasms TP63Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome-3;Orofacial cleft-8TPH Triosephosphate isomerase deficiencyTPM2 Distal arthrogryposis type 2B4TPO Deficiency of iodide peroxidase TPPI Ceroid lipofuscinosis neuronal-2; Childhood-onset autosomal recessive slowly progressive spinocerebellar ataxia; Inborn genetic diseases;Neuronal ceroid lipofuscinosisTPRN Autosomal recessive deafness-79TRAPPCH Limb-girdle muscular dystrophy type 28TRAPPC2 Spondyloepiphyseal dysplasia tarda TRDN Catecholaminergic polymorphic ventricular tachycardia-5;Catecholaminergic polymorphic ventricular tachycardia with or without muscle weakness TREXI, ATRIP, ATRIP-TREX1 Aicardi Goutieres syndrome-1; Chilblain lupus; Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations; TREXI-related disordersTRIM 14, NANS Genevieve type spondyloepimetaphyseal dysplasiaTRIM32,ASTN2 Limb-girdle muscular dystrophyTRIOBP Nonsyndromic hearing loss and deafnessTRIP 11 Achondrogenesis type IA; Goldblatt hypertension; Osteochondrodysplasia TRMUAcute infantile liver failure due to synthesis defect of mtDNA-encoded proteins TRNT1Retinitis pigmentosa and erythrocytic microcytosis; Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay TRPM4Cardiomyopathy; Progressive familial heart block type IB; TRPM4-related disordersTRPSI Trichorhinophalangeal dysplasia type 1TRPV4 Charcot-Marie-Tooth disease axonal type 2CTRPV6 Transient neonatal hyperparathyroidism TSCI Cortical dysplasia; Cortical tubers; Focal cortical dysplasia type II;Hereditary cancer-predisposing syndrome; Lymphangiomyomatosis;Multiple renal cysts; Renal cortical cysts; Renal insufficiency; Seizures;Tuberous sclerosis-1; Tuberous sclerosis syndrome; Urinary bladder cancer TSC2Focal cortical dysplasia type II; Lymphangiomyomatosis; Tuberous sclerosis-2; Tuberous sclerosis syndrome TSFMCombined oxidative phosphorylation deficiency-3; Primary dilated cardiomyopathyTSHB Secondary hypothyroidismTSHR Congenital nongoitrous hypothyroidism-1TSHZI Congenital aural atresia 302 WO 2024/216206 PCT/US2024/024492 TSPANI, POMGNT1 Congenital muscular alpha-dystroglycanopathy with brain and eye anomalies; Congenital muscular dystrophy-dystroglycanopathy with mental retardation type B3; Limb-girdle muscular dystrophy-dystroglycanopathy type C3; Muscle eye brain disease; POMGNT1-related disorders; Retinitis pigmentosa-76TSPAN12 Exudative vitreoretinopathy-5TSPAN7 X-linked mental retardation-58TSPEAR Hair/tooth type ectodermal dysplasia-14 with hypohidrosisTSPEAR-ASI, TSPEARHair/tooth type ectodermal dysplasia- 14 with hypohidrosis; Autosomal recessive deafness-98TTC19 Nuclear type 2 mitochondrial complex III deficiencyTTC21A Spermatogenic failure-37TTC21B, TTC21B-AS1 Short-rib thoracic dysplasia-4 with polydactylyTTC29 Spermatogenic failure-42TTC37 Trichohepatoenteric syndrome; Trichohepatoenteric syndrome- 1TTC7A Multiple gastrointestinal atresiasTTLL5 Cone-rod dystrophy- 19 TTN Cardiomyopathy; Cardiovascular phenotype; Dilated cardiomyopathy-1G; Limb-girdle muscular dystrophy type 21; Myotubular myopathy; Primary dilated cardiomyopathy; Tibial muscular dystrophy TTN-ASI, TTN Cardiovascular phenotype; Dilated cardiomyopathy-1G; Limb-girdle muscular dystrophy type 21; Primary dilated cardiomyopathy; TTN-related disordersTTN, LOC101927055 Primary dilated cardiomyopathy TTN, TTN-ASI Broad-based gait; Cardiomyopathy; Cardiovascular phenotype; Congenital muscular dystrophy; Decreased patellar reflex; Delayed gross motor development; Dilated cardiomyopathy- 1G; Dilated cardiomyopathy-IS; Distal muscle weakness; Familial dilated cardiomyopathy; Familial hypertrophic cardiomyopathy-9; Gowers sign; Heart murmur; Limb-girdle muscular dystrophy type 21; Muscular dystrophy; Myofibrillar myopathy-with early respiratory failure; Primary dilated cardiomyopathy; Proximal lower limb amyotrophy; Scoliosis; Severe muscular hypotonia; TTN-related disorder; Tibial muscular dystrophy; Waddling gait; Early-onset myopathy with fatal cardiomyopathy TTPAFamilial isolated deficiency of vitamin E; Friedreich-like ataxia with isolated vitamin E deficiencyTUB, RIC3 Retinal dystrophy and obesityTUBA3D,MZT2A Keratoconus-9TUBBS Oocyte maturation defect-2TULPI Leber congenital amaurosis; Retinitis pigmentosaTWIST 1 Craniosynostosis-1; Robinow-Sorauf syndrome; Saethre-Chotzen syndromeTXNL4A Burn-McKeown syndrome 303 WO 2024/216206 PCT/US2024/024492 TYK2 Tyrosine kinase 2 deficiency TYR Ocular albinism with sensorineural deafness; Inborn genetic diseases;Myopia; Nonsyndromic oculocutaneous albinism; Nystagmus;Oculocutaneous albinism; Oculocutaneous albinism type IB; Variation in skin/hair/eye pigmentation-3; Tyrosinase-negative oculocutaneous albinismTYRP1, LURAPIL-AS1 Oculocutaneous albinism type 3UBAPI Autosomal dominant spastic paraplegia-80UBE3A, SNHG14Angelman syndrome; History of neurodevelopmental disorder; Inborn genetic diseasesUBE3B Kaufman oculocerebrofacial syndromeUBRI Johanson-Blizzard syndromeUCP3 Severe obesity and type II diabetesUGTIA, UGT1A10, UGT1A8, UGT1A7, UGT1A6, UGT1A5, UGT1A9, UGT1A4, UGT1A1, UGT1A3 Crigler-Najjar syndrome type 11; Crigler-Najjar syndrome type 1UNCI 3D Familial hemophagocytic lymphohistiocytosis-3 UNC80Hypotonia-speech impairment-severe cognitive delay syndrome; Infantile hypotonia with psychomotor retardation and characteristic facies-2UNG Hyper-IgM syndrome type 5UPF3B X-linked syndromic mental retardation- 14 USHICAutosomal recessive deafness-18; Rare genetic deafness; Retinal dystrophy;Retinitis pigmentosa; Usher syndrome type 1C; Usher syndrome type 1 USH2A Abnormality of the upper limb; Abnormality of upper limb bone; Abnormality of upper limb joint; Anxiety; Brisk reflexes; Chronic pain; Cognitive impairment; Cone-rod dystrophy; Congenital sensorineural hearing impairment; Congenital stationary night blindness; Dislocated radial head; Distal arthrogryposis; Dysautonomia; Hearing impairment; High palate; Inborn genetic diseases; Macular dystrophy; Multiple joint contractures; Rare genetic deafness; Retinal dystrophy; Retinitis pigmentosa; Retinitis pigmentosa-39; Short stature; USH2A-related disorders; Usher syndrome type 2A; Usher syndrome type 2USH2A, USH2A-AS1Rare genetic deafness; Retinal dystrophy; Retinitis pigmentosa-39; USH2A- related disorders; Usher syndrome type 2AUSH2A, USH2A-AS2 Rare genetic deafness; Retinitis pigmentosa-39; Usher syndrome type 2AUSP18 Pseudo-TORCH syndrome-2USP27X X-linked mental retardation-105 304 WO 2024/216206 PCT/US2024/024492 USP9XUSP9X related disorders; X-linked female-restricted syndromic mental retardation-99 VCLDilated cardiomyopathy-lW; Familial hypertrophic cardiomyopathy-15; Primary dilated cardiomyopathy VHLFamilial erythrocytosis-2; Hereditary cancer-predisposing syndrome; Von Hippel-Lindau syndromeVHL, LOC107303340Familial erythrocytosis-2; Hereditary cancer-predisposing syndrome;Papillary renal cell carcinoma-1; Von Hippel-Lindau syndromeVIM, VIM-ASI Cataract-30; Congenital cataractVIPAS39 Arthrogryposis, renal dysfunction, and cholestasis-2VPS13A Choreoacanthocytosis VPS13B Abnormality of the eye; Cohen syndrome; Inborn genetic diseases;Intellectual disability; Microcephaly; Neutropenia; Progressive visual loss; Recurrent aphthous stomatitis; Retinal dystrophy; Short foot; Short stature; Small hand VPS33BArthrogryposis, renal dysfunction, and cholestasis-1; Inborn genetic diseases VRK2, FANCLComplementation group A Fanconi anemia; Complementation group L Fanconi anemiaVWF von Willebrand disorderWAC Desanto-Shinawi syndrome WASWiskott-Aldrich syndrome; X-linked severe congenital neutropenia; X- linked thrombocytopenia with normal platelets WDR35 Cranioectodermal dysplasia; Cranioectodermal dysplasia-2; Jeune thoracic dystrophy; Short-rib thoracic dysplasia-7 without polydactyly; Short rib polydactyly syndrome; Short rib polydactyly syndrome-5; Digenic short-rib thoracic dysplasia-7/20 with polydactyly; WDR35-related disorders WDR45Neurodegeneration with brain iron accumulation; Neurodegeneration with brain iron accumulation-5WDR72 Amelogenesis imperfectaWDR73 Galloway-Mowat syndrome- 1WEE2-AS1, WEE2 Oocyte maturation defect-5 WFSI Autosomal dominant nonsyndromic deafness-6; Diabetes mellitus and insipidus with optic atrophy and deafness; WFSl-related spectrum disorders; Wolfram-like syndrome WHRNAutosomal recessive deafness-31; Rare genetic deafness; Usher syndrome type 2DWRN Medulloblastoma; Werner syndrome WTIDrash syndrome; Frasier syndrome; Wilms tumor, aniridia, genitourinary anomalies, and mental retardation syndrome; Wilms tumor-1 WTI, LOG 107982234 Drash syndrome; Frasier syndrome; Pre-B-cell acute lymphoblastic leukemia; Wilms tumor, aniridia, genitourinary anomalies, and mental retardation syndrome; Wilms tumor-1XDH Deficiency of xanthine oxidase 305 WO 2024/216206 PCT/US2024/024492 XIAP X-linked lymphoproliferative syndrome-2XK McLeod neuroacanthocytosis syndromeXPA Xeroderma pigmentosum; Xeroderma pigmentosum group AXPC Xeroderma pigmentosum group C XRCC2 Complementation group U Fanconi anemia; Hereditary cancer syndrome; Hereditary breast and ovarian cancer syndrome; Hereditary cancer- predisposing syndrome; Ovarian neoplasmsXRCC4 Short stature, microcephaly, and endocrine dysfunctionXYLTI Desbuquois dysplasia-2XYLTI, LOC102723692 Desbuquois dysplasia-2XYLT2 Inborn genetic diseases; Autosomal recessive spondyloocular syndromeYY1AP1 Grange syndromeZBTB18 Autosomal dominant mental retardation-22ZDBF2 Nasopalpebral lipoma-coloboma syndromeZEB2 Mowat-Wilson syndromeZFYVE26 Hereditary spastic paraplegia- 15; Spastic paraplegiaZFYVE26,RDH12Abnormality of the eye; Leber congenital amaurosis-13; RDH12-related disorders; Retinal dystrophy; Retinitis pigmentosa ZMPSTE24Lethal tight skin contracture syndrome; Mandibuloacral dysplasia with type B lipodystrophy; ZMPSTE24-related disordersZNF408 Retinitis pigmentosa-72ZNF462 Craniosynostosis; Mental retardation; Weiss-Kruszka syndromeZNF711 ZNF711-related X-linked mental retardationZP1 Oocyte maturation defect- 1ZP2 Oocyte maturation defect-6 In an embodiment, the disease or disorder associated with a PTC is a lysosomal storage disease (e.g., Fabry disease, Gaucher disease,or Niemann-Pick disease). In some embodiments, the disease or disorder associated with a PTC is Fabry disease. In an embodiment, uponadministration of a TREM (e.g., a TREM described herein) to a cell or subject, the level of a GLA protein in the cell or subject is modulated, e.g., increased, by about 0.1%, 0.5%, 1%, 2%, 3%, 4% 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more, e.g., compared with a reference value (e.g., level of a GLA protein in a healthy, non-Fabry disease fibroblast).In some embodiments, the disease or disorder associated with a PTC is a blood clottingdisorder, e.g., Hemophilia B. In an embodiment, upon administration of a TREM (e.g., a TREM described herein) to a cell or subject, the level of a Factor IX (FIX) protein in the cell or subject is modulated, e.g., increased, by about 0.1%, 0.5%, 1%, 2%, 3%, 4% 5%, 6%, 7%, 8%, 9%, 306 WO 2024/216206 PCT/US2024/024492 %, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more, e.g., compared with a reference value (e.g., level of a FIX protein in a healthy, non-disease cell).In some embodiments, the disease or disorder associated with a PTC is an autosomal recessive disorder, such as neuronal ceroid lipofuscinosis type 2 (CNL2). In an embodiment, upon administration of a TREM (e.g., a TREM described herein) to a cell or subject, the level of a tripeptidyl peptidase 1 (TPP1) protein in the cell or subject is modulated, e.g., increased, by about 0.1%, 0.5%, 1%, 2%, 3%, 4% 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more, e.g., compared with a reference value (e.g., level of a TPPI protein in a healthy, non-disease cell).In some embodiments, the disease or disorder associated with a PTC is a disease or disorder associated with hearing loss, such as Usher syndrome (e.g., Usher syndrome type IF). In an embodiment, upon administration of a TREM (e.g., a TREM described herein) to a cell or subject, the level of a protocadherin 15 precursor (PCDH15) protein in the cell or subject is modulated, e.g., increased, by about 0.1%, 0.5%, 1%, 2%, 3%, 4% 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more, e.g., compared with a reference value (e.g., level of a PCDH15 protein in a healthy, non-disease cell).In an embodiment, the disease or disorder associated with a PTC is a proliferative disease, such as a benign neoplasm or a cancer. In an embodiment, the proliferative disease is associated with a benign neoplasm. For example, a benign neoplasm may include adenoma, fibroma, hemangioma, tuberous sclerosis, and lipoma. All types of benign neoplasms disclosed herein or known in the art are contemplated as being within the scope of the disclosure.In an embodiment, the proliferative disease is a cancer. As used herein, the term "cancer " refers to a malignant neoplasm (Stedman ’s Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990). All types of cancers disclosed herein or known in the art are contemplated as being within the scope of the disclosure. Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary 307 WO 2024/216206 PCT/US2024/024492 cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma;endotheliosarcoma (e.g., Kaposi ’s sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett ’s adenocarcinoma); Ewing ’s sarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma); familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer), e.g., adenoid cystic carcinoma (ACC)); hematopoietic cancers (e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphoma such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenstrom ’s macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T-lymphoblastic lymphoma/leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); a mixture of one or more leukemia/lymphoma as described above; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma 308 WO 2024/216206 PCT/US2024/024492 chain disease, mu chain disease); hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastic tumors; immunocytic amyloidosis; kidney cancer (e.g., nephroblastoma a.k.a. Wilms ’ tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (EMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors); penile cancer (e.g., Paget ’s disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes; intraepithelial neoplasms; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget ’s disease of the vulva). In some embodiments, the cancer is a solid tumor, such as a sarcoma or a carcinoma (e.g., lung cancer, brain cancer, breast cancer, bladder cancer, prostate cancer, colon cancer, rectal cancer).In another aspect, the present disclosure features methods of treating a disease or disorder in a cell or subject by administration of a TREM (e.g., a TREM described herein) to the cell or subject. Exemplary diseases or disorders include hemophilias, aminoacidopathies, metal storage 309 WO 2024/216206 PCT/US2024/024492 disorders, peroxisome biogenesis disorder, progressive rare lung disease, diseases related to lipid metabolism, diseases related to galactose metabolism, systemic organic acidemias, urea cycle disorders, cholestastis disorders, bilirubin metabolism disorders, lysososomal storage disorders, glycogen storage diseases, and oxalate metabolism disorders. In an embodiment, the disease or disorder is a hemophilia, e.g., hemophilia A or hemophilia B. In an embodiment, the disease or disorder is an aminoacidopathy, e.g., tyrosinemia type 1, tyrosinemia type 2, tyrosinemia type 3, maple syrup urine disease, alkaptonuria, or phenylketonuria. In an embodiment, the disease or disorder is a systemic organic acidemia, e.g., methylmalonic acidemia (MMUT), methylmalonic acidemia (non-MMUT), propionic acidemia type A, propionic acidemia type B, or isovaleric acidemia. In an embodiment, the disease or disorder is a urea cycle disorder, e.g, argininosuccinate lyase deficiency, argininosuccinate lyase deficiency-D, citrullinemia type 1, citrullinemiatype 2, carbamoyl phosphate synthetase-D, ornithine transcarbamylase, arginemia, or hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome. In an embodiment, the disease or disorder is lysosomal storage disorder, e.g., mucopolysaccharidosis 1, mucopolysaccharidosis 2, Fabry disease, lysosomal acid lipas deficiency, Pompe disease, Gaucher disease, Niemann Pick A, or Niemann Pick B. In an embodiment, the disease or disorder is a bilirubin metabolism disorder, e.g., Crigler-Najjar syndrome. In an embodiment, the disease or disorder is a cholestastis disorder, e.g., progressive familial intrahepatic cholestasis (PFIC) type 1, PFIC type 2, or PFIC type 3. In an embodiment, the disease or disorder is a disease related to lipid metabolism, e.g., sitosterolemia (ABCG5) or sitosterolemia (ABCG8). In an embodiment, the disease or disorder is a glycogen storage disease, e.g., glycogen storage disease la, glycogen storage disease lb, or glycogen storage disease 3a. In an embodiment, the disease or disorder is a metal storage disorder, e.g., Wilson disease or hereditary hemochromatosis. In an embodiment, the disease or disorder is a progressive rare lung disease, e.g., alpha- 1 antitrypsin deficiency. In an embodiment, the disease or disorder is a peroxisome biogenesis disorder, e.g., PBD RCDP1. In an embodiment, the disease or disorder is an oxalate metabolism disorder, e.g, primary hyperoxaluria type 1, primary hyperoxaluria type 2, or primary hyperoxaluria type 3 . In an embodiment, the disease or disorder is a congenital disorder related to Notch signaling, e.g., Alagille syndrome. In an embodiment, the disease or disorder is an amyloidosis, e.g., familial amyloid polyneuropathy. 310 WO 2024/216206 PCT/US2024/024492 In one aspect, the present disclosure features a method of treating a disease or disorder in a subject, the method comprising administering to the subject a TREM comprising the nucleotide sequence of any one of the TREMS listed in FIG. 3 . In an embodiment, the disease or disorder is selected from a hemophilia, aminoacidopathy, metal storage disorder, peroxisome biogenesis disorder, progressive rare lung disease, disease related to lipid metabolism, disease related to galactose metabolism, systemic organic acidemia, urea cycle disorder, cholestastis disorder, bilirubin metabolism disorder, lysososomal storage disorder, glycogen storage disease, and oxalate metabolism disorder. In an embodiment, the TREM comprises the sequence of any one of SEQ IDNO: 622, 623, 624, 4249, 4386, 4834, 5630, 6707, 6749, 6947, or 8051, or a fragment or variant thereof.

Method of making TREMs, TREM core fragments, and TREM fragments In vitro methods for synthesizing oligonucleotides are known in the art and can be used to make a TREM, a TREM core fragment or a TREM fragment disclosed herein. For example, a TREM, TREM core fragment or TREM fragment can be synthesized using solid state synthesis or liquid phase synthesis.In an embodiment, a TREM, a TREM core fragment or a TREM fragment made according to an in vitro synthesis method disclosed herein has a different modification profile compared to a TREM expressed and isolated from a cell, or compared to a naturally occurring tRNA.An exemplary method for making a modified TREM is provided in Example 1. The method provided in Example I can also be used to make a synthetic TREM core fragment or synthetic TREM fragment. Additional synthetic methods are disclosed in Hartsei SA et al., (2005) Oligonucleotide Synthesis, 033-050, the entire contents of which are hereby incorporated by reference.

TREM composition In an embodiment, a TREM composition, e.g., a TREM pharmaceutical composition, comprises a pharmaceutically acceptable excipient. Exemplary excipients include those provided in the FDA Inactive Ingredient Database (https://www.accessdata.fda.gov/scripts/cder/iig/index . Cfm). 311 WO 2024/216206 PCT/US2024/024492 In an embodiment, a TREM composition, e.g., a TREM pharmaceutical composition, comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100 or 150 grams of TREM, TREM core fragment or TREM fragment. In an embodiment, a TREM composition, e.g., a TREM pharmaceutical composition, comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50 or 100 milligrams of TREM, TREM core fragment or TREM fragment.In an embodiment, a TREM composition, e.g, a TREM pharmaceutical composition, is at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 95 or 99% dry weight TREMs, TREM core fragments or TREM fragments.In an embodiment, a TREM composition comprises at least 1 x 106 TREM molecules, at least 1 x 107 TREM molecules, at least 1 x 108 TREM molecules or at least 1 x 109 TREM molecules.In an embodiment, a TREM composition comprises at least 1 x 106 TREM core fragment molecules, at least 1 x 107 TREM core fragment molecules, at least 1 x 108 TREM core fragment molecules or at least 1 x 109 TREM core fragment molecules.In an embodiment, a TREM composition comprises at least 1 x 106 TREM fragment molecules, at least 1 x 107 TREM fragment molecules, at least 1 x 108 TREM fragment molecules or at least 1 x 109 TREM fragment molecules.In an embodiment, a TREM composition produced by any of the methods of making disclosed herein can be charged with an amino acid using an in vitro charging reaction as known in the art.In an embodiment, a TREM composition comprise one or more species of TREMs, TREM core fragments, or TREM fragments. In an embodiment, a TREM composition comprises a single species of TREM, TREM core fragment, or TREM fragment. In an embodiment, a TREM composition comprises a first TREM, TREM core fragment, or TREM fragment species and a second TREM, TREM core fragment, or TREM fragment species. In an embodiment, the TREM composition comprises X TREM, TREM core fragment, or TREM fragment species, wherein X=2, 3, 4, 5, 6, 7, 8, 9, or 10.In an embodiment, the TREM, TREM core fragment, or TREM fragment has at least 70, 75, 80, 85, 90, or 95, or has 100%, identity with a sequence encoded by a nucleic acid in Table 1.In an embodiment, the TREM comprises a consensus sequence provided herein. 312 WO 2024/216206 PCT/US2024/024492 A TREM composition can be formulated as a liquid composition, as a lyophilized composition or as a frozen composition.In some embodiments, a TREM composition can be formulated to be suitable for pharmaceutical use, e.g., a pharmaceutical TREM composition. In an embodiment, a pharmaceutical TREM composition is substantially free of materials and/or reagents used to separate and/or purify a TREM, TREM core fragment, or TREM fragment.In some embodiments, a TREM composition can be formulated with water for injection. In some embodiments, a TREM composition formulated with water for injection is suitable for pharmaceutical use, e.g., comprises a pharmaceutical TREM composition.

TREM characterization A TREM, TREM core fragment, or TREM fragment, or a TREM composition, e.g., a pharmaceutical TREM composition, produced by any of the methods disclosed herein can be assessed for a characteristic associated with the TREM, TREM core fragment, or TREM fragment or the TREM composition, such as purity, sterility, concentration, structure, or functional activity of the TREM, TREM core fragment, or TREM fragment. Any of the above- mentioned characteristics can be evaluated by providing a value for the characteristic, e.g., by evaluating or testing the TREM, TREM core fragment, or TREM fragment, or the TREM composition, or an intermediate in the production of the TREM composition. The value can also be compared with a standard or a reference value. Responsive to the evaluation, the TREM composition can be classified, e.g., as ready for release, meets production standard for human trials, complies with ISO standards, complies with cGMP standards, or complies with other pharmaceutical standards. Responsive to the evaluation, the TREM composition can be subjected to further processing, e.g., it can be divided into aliquots, e.g., into single or multi- dosage amounts, disposed in a container, e.g, an end-use vial, packaged, shipped, or put into commerce. In embodiments, in response to the evaluation, one or more of the characteristics can be modulated, processed or re-processed to optimize the TREM composition. For example, the TREM composition can be modulated, processed or re-processed to (i) increase the purity of the TREM composition; (ii) decrease the amount of fragments in the composition; (iii) decrease the amount of endotoxins in the composition; (iv) increase the in vitro translation activity of the composition; (v) increase the TREM concentration of the composition; or (vi) inactivate or 313 WO 2024/216206 PCT/US2024/024492 remove any viral contaminants present in the composition, e.g., by reducing the pH of the composition or by filtration.In an embodiment, the TREM, TREM core fragment, or TREM fragment (e.g., TREM composition or an intermediate in the production of the TREM composition) has a purity of at least 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, i.e., by mass.In an embodiment, the TREM (e.g., TREM composition or an intermediate in the production of the TREM composition) has less than 0.1%, 0,5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25% TREM fragments relative to full length TREMs.In an embodiment, the TREM, TREM core fragment, or TREM fragment (e.g., TREM composition or an intermediate in the production of the TREM composition) has low levels or absence of endotoxins, e.g., a negative result as measured by the Limulus amebocyte lysate (LAL) test.In an embodiment, the TREM, TREM core fragment, or TREM fragment (e.g., TREM composition or an intermediate in the production of the TREM composition) has in-vitro translation activity, e.g., as measured by an assay described in Examples 12-13.In an embodiment, the TREM, TREM core fragment, or TREM fragment (e.g., TREM composition or an intermediate in the production of the TREM composition) has a TREM concentration of at least 0.1 ng/mL, 0.5 ng/mL, 1 ng/mL, 5 ng/mL, 10 ng/mL, 50 ng/mL, 0.ug/mL, 0.5 ug/mL, 1 ug/mL, 2 ug/mL, 5 ug/mL, 10 ug/mL, 20 ug/mL, 30 ug/mL, 40 ug/mL, ug/mL, 60 ug/mL, 70 ug/mL, 80 ug/mL, 100 ug/mL, 200 ug/mL, 300 ug/mL, 500 ug/mL, 10ug/mL, 5000 ug/mL, 10,000 ug/mL, or 100,000 ug/mL.In an embodiment, the TREM, TREM core fragment, or TREM fragment (e.g., TREM composition or an intermediate in the production of the TREM composition) is sterile, e.g., the composition or preparation supports the growth of fewer than 100 viable microorganisms as tested under aseptic conditions, the composition or preparation meets the standard of USP <71>, and/or the composition or preparation meets the standard of USP <85>.In an embodiment, the TREM, TREM core fragment, or TREM fragment (e.g., TREM composition or an intermediate in the production of the TREM composition) has an undetectable level of viral contaminants, e.g., no viral contaminants. In an embodiment, any viral contaminant, e.g., residual virus, present in the composition is inactivated or removed. In an 314 WO 2024/216206 PCT/US2024/024492 embodiment, any viral contaminant, e.g., residual virus, is inactivated, e.g., by reducing the pH of the composition. In an embodiment, any viral contaminant, e.g., residual virus, is removed, e.g., by filtration or other methods known in the field.

TREM administration Any TREM composition or pharmaceutical composition described herein can be administered to a cell, tissue or subject, e.g., by direct administration to a cell, tissue and/or an organ in vitro, ex-vivo or in vivo. In-vivo administration may be via, e.g., by local, systemic and/or parenteral routes, for example intravenous, subcutaneous, intraperitoneal, intrathecal, intramuscular, ocular, nasal, urogenital, intradermal, dermal, enteral, intravitreal, intracerebral, intrathecal, or epidural.Vectors and CarriersIn some embodiments the TREM, TREM core fragment, or TREM fragment or TREM composition described herein, is delivered to cells, e.g. mammalian cells or human cells, using a vector. The vector may be, e.g., a plasmid or a virus. In some embodiments, delivery is in vivo, in vitro, ex vivo, or in situ. In some embodiments, the virus is an adeno associated virus (AAV), a lentivirus, or an adenovirus. In some embodiments, the system or components of the system are delivered to cells with a viral-like particle or a virosome. In some embodiments, the delivery uses more than one virus, viral-like particle or virosome.CarriersA TREM, a TREM composition or a pharmaceutical TREM composition described herein may comprise, may be formulated with, or may be delivered in, a carrier.Viral vectorsThe carrier may be a viral vector (e.g., a viral vector comprising a sequence encoding a TREM, a TREM core fragment or a TREM fragment). The viral vector may be administered to a cell or to a subject (e.g., a human subject or animal model) to deliver a TREM, a TREM core fragment or a TREM fragment, a TREM composition or a pharmaceutical TREM composition.A viral vector may be systemically or locally administered (e.g., injected). Viral genomes provide a rich source of vectors that can be used for the efficient delivery of exogenous genes into a mammalian cell. Viral genomes are known in the art as useful vectors for delivery because the polynucleotides contained within such genomes are typically incorporated into the 315 WO 2024/216206 PCT/US2024/024492 nuclear genome of a mammalian cell by generalized or specialized transduction. These processes occur as part of the natural viral replication cycle, and do not require added proteins or reagents in order to induce gene integration. Examples of viral vectors include a retrovirus (e.g, Retroviridae family viral vector), adenovirus (e.g., Ad5, Ad26, Ad34, Ad35, and Ad48), parvovirus (e.g., adeno-associated viruses), coronavirus, negative strand RNA viruses such as orthomyxovirus (e.g., influenza virus), rhabdovirus (e.g, rabies and vesicular stomatitis virus), paramyxovirus (e.g., measles and Sendai), positive strand RNA viruses, such as picomavirus and alphavirus, and double stranded DNA viruses including adenovirus, herpesvims (e.g., Herpes Simplex vims types 1 and 2, Epstein-Barr vims, cytomegalovirus, replication deficient herpes vims), and poxvirus (e.g., vaccinia, modified vaccinia Ankara (MVA), fowlpox and canarypox). Other viruses include Norwalk vims, togavims, flavivirus, reovimses, papovavirus, hepadnavirus, human papilloma vims, human foamy vims, and hepatitis vims, for example. Examples of retrovimses include: avian leukosis-sarcoma, avian C-type vimses, mammalian C- type, B-type vimses, D-type vimses, oncoretroviruses, HTLV-BLV group, lentivims, alpharetrovirus, gammaretrovirus, spumavims (Coffin, J. M., Retroviridae: The vimses and their replication, Virology (Third Edition) Lippincott-Raven, Philadelphia, 1996). Other examples include murine leukemia vimses, murine sarcoma vimses, mouse mammary tumor vims, bovine leukemia vims, feline leukemia vims, feline sarcoma vims, avian leukemia vims, human T-cell leukemia vims, baboon endogenous vims, Gibbon ape leukemia vims, Mason Pfizer monkey vims, simian immunodeficiency vims, simian sarcoma vims, Rous sarcoma vims and lentiviruses. Other examples of vectors are described, for example, in US Patent No. 5,801,030, the teachings of which are incorporated herein by reference. In some embodiments the system or components of the system are delivered to cells with a viral-like particle or a virosome.Cell and vesicle-based carriersA TREM, a TREM core fragment or a TREM fragment, a TREM composition or a pharmaceutical TREM composition described herein can be administered to a cell in a vesicle or other membrane-based carrier.In embodiments, a TREM, a TREM core fragment or a TREM fragment, or TREM composition, or pharmaceutical TREM composition described herein is administered in or via a cell, vesicle or other membrane-based carrier. In one embodiment, the TREM, TREM core fragment, TREM fragment, or TREM composition or pharmaceutical TREM composition can be 316 WO 2024/216206 PCT/US2024/024492 formulated in liposomes or other similar vesicles. Liposomes are spherical vesicle structures composed of a uni- or multilamellar lipid bilayer surrounding internal aqueous compartments and a relatively impermeable outer lipophilic phospholipid bilayer. Liposomes may be anionic, neutral or cationic. Liposomes are biocompatible, nontoxic, can deliver both hydrophilic and lipophilic drug molecules, protect their cargo from degradation by plasma enzymes, and transport their load across biological membranes and the blood brain barrier (BBB) (see, e.g, Spuch and Navarro, Journal of Drug Delivery, vol. 2011, Article ID 469679, 12 pages, 2011. doi; 10.1155/2011/469679 for review).Vesicles can be made from several different types of lipids; however, phospholipids are most commonly used to generate liposomes as drug carriers. Methods for preparation of multilamellar vesicle lipids are known in the art (see for example U.S. Pat. No. 6,693,086, the teachings of which relating to multilamellar vesicle lipid preparation are incorporated herein by reference). Although vesicle formation can be spontaneous when a lipid film is mixed with an aqueous solution, it can also be expedited by applying force in the form of shaking by using a homogenizer, sonicator, or an extrusion apparatus (see, e.g., Spuch and Navarro, Journal of Drug Delivery, vol. 2011, Article ID 469679, 12 pages, 2011. doi:10. 1155/2011/469679 for review). Extruded lipids can be prepared by extruding through filters of decreasing size, as described in Templeton et al., Nature Biotech, 15:647-652, 1997, the teachings of which relating to extruded lipid preparation are incorporated herein by reference.Lipid Nanoformulalions Lipid-based carriersLipid nanoparticles are another example of a carrier that provides a biocompatible and biodegradable delivery system for the TREM, TREM core fragment, TREM fragment, or TREM composition or pharmaceutical TREM composition described herein. Nanostructured lipid carriers (NLCs) are modified solid lipid nanoparticles (SLNs) that retain the characteristics of the SLN, improve drug stability and loading capacity, and prevent drug leakage. Polymer nanoparticles (PNPs) are an important component of drug delivery. These nanoparticles can effectively direct drug delivery to specific targets and improve drug stability and controlled drug release. Lipid-polymer nanoparticles (PLNs), a new type of carrier that combines liposomes and polymers, may also be employed. These nanoparticles possess the complementary advantages of PNPs and liposomes. A PLN is composed of a core-shell structure; the polymer core provides a stable structure, and the phospholipid shell offers good biocompatibility. As such, the two 317 WO 2024/216206 PCT/US2024/024492 components increase the drug encapsulation efficiency rate, facilitate surface modification, and prevent leakage of water-soluble drugs. For a review, see, e.g., Li et al. 2017, Nanomaterials 7, 122; doi:10.3390/nano7060122.Exemplary lipid nanoparticles are disclosed in International Application PCT/US2014/053907, the entire contents of which are hereby incorporated by reference. For example, an LNP described in paragraphs [403-406] or [410-413] of PCT/US2014/053907 can be used as a carrier for the TREM, TREM core fragment, TREM fragment, or TREM composition or pharmaceutical TREM composition described herein.Additional exemplary lipid nanoparticles are disclosed in U.S. Patent 10,562,849 the entire contents of which are hereby incorporated by reference. For example, an LNP of formula (I) as described in columns 1-3 of U.S. Patent 10,562,849 can be used as a carrier for the TREM, TREM core fragment, TREM fragment, or TREM composition or pharmaceutical TREM composition described herein.Lipids that can be used in nanoparticle formations (e.g., lipid nanoparticles) include, for example those described in Table 4 of WO2019217941, which is incorporated by reference, e.g., a lipid-containing nanoparticle can comprise one or more of the lipids in Table 4 of WO2019217941. Lipid nanoparticles can include additional elements, such as polymers, such as the polymers described in Table 5 of WO2019217941, incorporated by reference.In some embodiments, conjugated lipids, when present, can include one or more of PEG- di acylglycerol (DAG) (such as l-(m on om ethoxy-poly ethyl eneglycol)-2, 3- dimyristoylglycerol (PEG-DMG)), PEG-dialkyloxypropyl (DAA), PEG-phospholipid, PEG- ceramide (Cer), a pegylated phosphatidylethanoloamine (PEG-PE), PEG succinate diacylglycerol (PEGS-DAG) (such as 4-0-(2’,3’-di(tetradecanoyloxy)propyl-l-0-(w- methoxy(polyethoxy)ethyl) butanedioate (PEG-S-DMG)), PEG dialkoxypropylcarbam, N- (carbonyl-methoxypoly ethylene glycol 2000)- ,2-distearoyl-sn-glycero-3-phosphoethanolamine sodium salt, and those described in Table 2 of WO2019051289 (incorporated by reference), and combinations of the foregoing.In some embodiments, sterols that can be incorporated into lipid nanoparticles include one or more of cholesterol or cholesterol derivatives, such as those in W02009/127060 or US2010/0130588, which are incorporated by reference. Additional exemplary sterols include phytosterols, including those described in Eygeris et al (2020), incorporated herein by reference. 318 WO 2024/216206 PCT/US2024/024492 Cationic Lipids (Positively Charged) and Ionizable LipidsIn some embodiments, the lipid-based carrier (or lipid nanoformulation) comprises one or more cationic lipids, e.g., a cationic lipid that can exist in a positively charged or neutral form depending on pH, or an amine-containing lipid that can be readily protonated. In some embodiments, the cationic lipid is a lipid capable of being positively charged, e.g, under physiological conditions.Exemplary cationic lipids include one or more amine group(s) which bear the positive charge. Examples of positively charged (cationic) lipids include, but are not limited to, N,Ndimethyl-N,NEdioctacyl ammonium bromide (DDAB) and chloride DDAC), N-(l-(2,3- dioleyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTMA), 3p־[N־(N(Ndimethylaminoethyl)carbamoyl) cholesterol (DC-chol), l,2-dioleoyloxy-3-[trimethylammonio]- propane (DOTAP), l,2-dioctadecyloxy-3-[trimethylammonio]-propane (DSTAP), and 1,2- dioleoyloxypropyl-3-dimethyl-hydroxy ethyl ammonium chloride (DORI), N,N-dioleyl-N,N- dimethyl ammonium chloride ( DODA C), N,N-dimeihyl-2,3-dio1eyloxy )propylamine (DODMA), l,2-Dioleoyl-3-Dimethylammonium-propane (DODAP), l,2-Dioleoylcarbamyl-3- Dimethyiammonium-propasae (DOCDAP), l,2-DiHneoyl-3-Dime1hylammonium-propane (DLINDAP), 3-Dimethylamino-2-(Cholest-5-en-3-beta-oxybutan-4-oxy)-l-(cis,cis-9, 12- octadecadienoxy )propane (CLinDMA), 2-[5'-(cholest-5-en-3-beta-oxy )-3'-oxapentoxy )-3- dimethyl- 1-(cis, cis-9'J2'-octadecadienoxy)propane (CpLin DMA), N,N-Dimethyl-3,4- dioleyloxybenzylamine (DMOBA), and the cationic lipids described in e.g. Martin et al., Current Pharmaceutical Design, pages 1-394, which is herein incorporated by reference in its entirety. In some embodiments, the lipid-based carrier (or lipid nanoformulation) comprises more than one cationic lipid.In some embodiments, the lipid-based carrier (or lipid nanoformulation) comprises a cationic lipid having an effective pKa over 6.0. In some embodiments, the lipid-based carrier (or lipid nanoformulation) further comprises a second cationic lipid having a different effective pKa (e.g., greater than the first effective pKa) than the first cationic lipid.In some embodiments, cationic lipids that can be used in the lipid-based carrier (or lipid nanoformulation) include, for example those described in Table 4 of WO 2019/217941, which is incorporated by reference.In some embodiments, the cationic lipid is an ionizable lipid (e.g., a lipid that is 319 WO 2024/216206 PCT/US2024/024492 protonated at low pH, but that remains neutral at physiological pH). In some embodiments, the lipid-based carrier (or lipid nanoformulation) may comprise one or more additional ionizable lipids, different than the ionizable lipids described herein. Exemplary ionizable lipids include,but are not limited to, (SM-102), (ALC-0315), (Lipid 10), (Lipid A9), and (DLin-MC3-DMA), (see WO 2017/004143A1, which is incorporated herein by reference in its entirety). 320 WO 2024/216206 PCT/US2024/024492 In some embodiments, the lipid-based carrier (or lipid nanoformulation) further comprises one or more compounds described by WO 2021/113777 (e.g., a lipid of Formula (3) such as a lipid of Table 3 of WO 2021/113777), which is incorporated herein by reference in its entirety.In one embodiment, the ionizable lipid is a lipid disclosed in Hou, X., et al. Nat Rev Mater 6, 1078-1094 (2021). https ://doi.org/l 0.103 8/s4 1578-021 -003 58-0 (e.g., L319, C12-200, and DLin-MC3-DMA), (which is incorporated by reference herein in its entirety).Examples of other ionizable lipids that can be used in lipid-based carrier (or lipid nanoformulation) include, without limitation, one or more of the following formulas: X of US 2016/0311759; I of US 20150376115 or in US 2016/0376224; Compound 5 or Compound 6 in US 2016/0376224; I, IA, or II of US 9,867,888; 1, II or ill of US 2016/0151284; 1, IA, II, or IIA of US 2017/0210967; I-c of US 2015/0140070; A of US 2013/0178541; I of US 2013/03035or US 2013/0123338; I of US 2015/0141678; II, III, IV, or V of US 2015/0239926; I of US 2017/0119904; I or II of WO 2017/117528; A of US 2012/0149894; A of US 2015/0057373; A of WO 2013/116126; A of US 2013/0090372; A of US 2013/0274523; A of US 2013/0274504; A of US 2013/0053572; A of WO 2013/016058; A of WO 2012/162210; I of US 2008/042973; I, II, III, or IV of US 2012/01287670; I or II of US 2014/0200257; I, II, or III of US 2015/0203446; I or III of US 2015/0005363; I, IA, IB, IC, ID, II, IIA, IIB, IIC, IID, or III-XXIV of US 2014/0308304; of US 2013/0338210; 1, II, III, or IV of WO 2009/132131; A of US 2012/01011478; lor XXXV of US 2012/0027796; XIV or XVII of US 2012/0058144; of US 2013/0323269; I of US 2011/0117125; 1, II, or III of US 2011/0256175; I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII of US 2012/0202871; 1, II, III, IV, V, VI, VII, VIII, X, XII, XIII, XIV, XV, or XVI of US 2011/0076335; I or II of US 2006/008378; I of WO2015/074085 (e.g, ATX-002); I of US 2013/0123338; I or X-A-Y-Z of US 2015/0064242; XVI, XVII, or XVIII of US 2013/0022649; 1, II, or III of US 2013/0116307; I, II, or III of US 2013/0116307; I or II of US 2010/0062967; I-X of US 2013/0189351; I of US 2014/0039032; V of US 2018/0028664; I of US 2016/0317458; I of US 2013/0195920; 5, 6, or 10 of US 10,221,127; 111-3 of WO 2018/081480; 1-5 or 1-8 of WO 2020/081938; I of WO 2015/199952 (e.g, compound 6 or 22) and Table 1 therein; 18 or 25 of US 9,867,888; A of US 2019/0136231; II of WO 2020/219876; of US 2012/0027803; OF-02 of US 2019/0240349; 23 of US 10,086,013; CKK-E12/A6 of Miao et al (2020); C12-200 of WO 2010/053572; 7C1 of Dahlman et al (2017); 304-013 or 503- 321 WO 2024/216206 PCT/US2024/024492 013 of Whitehead et al; TS-P4C2 of U 89,708,628; I of WO 2020/106946; I of WO 2020/106946; (1), (2), (3), or (4) of WO 2021/113777; and any one of Tables 1-16 of WO 2021/113777, all of which are incorporated herein by reference in their entirety.In some embodiments, the lipid-based carrier (or lipid nanoformulation) further includes biodegradable ionizable lipids, for instance, (9Z,12Z)-3-((4,4-bis(octyloxy)butanoyl)oxy)-2-((((3- (diethylamino)propoxy)carbonyl)oxy)methyl)propyl octadeca-9,12-dienoate, also called 3- ((4,4- bis(octyloxy)butanoyl)oxy)-2-((((3-(diethylamino)propoxy)carbonyl)oxy)methyl)propyl (9Z,12Z)-octadeca-9,12-dienoate). See, e.g., lipids of WO 2019/067992, WO 2017/173054, WO 2015/095340, and WO 2014/136086, which are incorporated herein by reference in their entirety.In some embodiments, the lipid particle comprises an ionizable lipid, a non-cationic lipid, a conjugated lipid that inhibits aggregation of particles, and a sterol. The amounts of these components can be varied independently and to achieve desired properties. For example, in some embodiments, the lipid nanoparticle comprises an ionizable lipid is in an amount from about 20 mol % to about 90 mol % of the total lipids (in other embodiments it may be 20-70% (mol), 30-60% (mol) or 40-50% (mol); about 50 mol % to about 90 mol % of the total lipid present in the lipid nanoparticle), a non-cationic lipid in an amount from about 5 mol % to about mol % of the total lipids, a conjugated lipid in an amount from about 0.5 mol % to about mol % of the total lipids, and a sterol in an amount from about 20 mol % to about 50 mol % of the total lipids. The ratio of total lipid to nucleic acid can be varied as desired. For example, the total lipid to nucleic acid (mass or weight) ratio can be from about 10: 1 to about 30: 1.In some embodiments, the lipid to nucleic acid ratio (mass/mass ratio; w/w ratio) can be in the range of from about 1 : 1 to about 25: 1, from about 10: 1 to about 14: 1, from about 3 : to about 15: 1, from about 4: 1 to about 10: 1, from about 5: 1 to about 9; 1, or about 6: 1 to about 9:1. The amounts of lipids and nucleic acid can be adjusted to provide a desired N/P ratio, for example, N/P ratio of 3, 4, 5, 6, 7, 8, 9, 10 or higher. Generally, the lipid nanoparticle formulation ’s overall lipid content can range from about 5 mg/ml to about 30 mg/mL.Some non-limiting example of lipid compounds that may be used (e.g., in combination with other lipid components) to form lipid nanoparticles for the delivery of compositions described herein, e.g., nucleic acid (e.g., RNA) described herein includes, 322 WO 2024/216206 PCT/US2024/024492 - - - - - - - ■ (i) In some embodiments an LNP comprising Formula (i) is used to deliver a TREM composition described herein to the liver and/or hepatocyte cells. - - - - - - - - (ii)In some embodiments an LNP comprising Formula (ii) is used to deliver a TREM 5composition described herein to the liver and/or hepatocyte cells.

In some embodiments an LNP comprising Formula (iii) is used to deliver a TREMcomposition described herein to the liver and/or hepatocyte cells. ./-x /x., .A. A^ , •-'x -L ,0. 1 ,c«3A ,..■A X/' xv ''־• -־י — '-(iv) (v)In some embodiments an LNP comprising Formula (v) is used to deliver a TREM composition described herein to the liver and/or hepatocyte cells. 323 WO 2024/216206 PCT/US2024/024492 In some embodiments an LNP comprising Formula (vi) is used to deliver a TREM composition described herein to the liver and/or hepatocyte cells.

In some embodiments an LNP comprising Formula (viii) is used to deliver a TREM composition described herein to the liver and/or hepatocyte cells.

In some embodiments an LNP comprising Formula (ix) is used to deliver a TREMcomposition described herein to the liver and/or hepatocyte cells. 324 WO 2024/216206 PCT/US2024/024492 wherein X1 is 0, NR1, or a direct bond, X2 is C2-5 alkylene, X3 is C(=O) or a direct bond, R1 is H or Me, R3 is Ci-3 alkyl, R2 is Ci-3 alkyl, or R2 taken together with the nitrogen atom to which it is attached and 1-3 carbon atoms of X2 form a 4-, 5-, or 6-membered ring, or X1 is NR1, R1 and R2 taken together with the nitrogen atoms to which they are attached form a 5- or 6-membered ring, or R2 taken together with R3 and the nitrogen atom to which they are attached form a 5-, 6-, or 7-membered ring, Y1 is C2-12 alkylene, Y2 is selected fromO (in either orientation), (in either orientation), (in eitherorientation),O* ־'{ ן .ןn is 0 to 3, R is Ci-15 alkyl, Z is Ci-6 alkylene or a direct bond, is י (in eitherorientation) or absent, provided that if Z1 is a direct bond, Z2 is absent; R5 is C5-9 alkyl or C6-alkoxy, R6 is C5-9 alkyl or C6-10 alkoxy, W is methylene or a direct bond, and R7 is H or Me, or a salt thereof, provided that if R3 and R2 are C2 alkyls, X1 is 0, X2 is linear C3 alkylene, X3 is/x R4C(=0), Y1 is linear Ce alkylene, (Y2 )n-R 4 is ; rN==/X==Z , r4 is 1؛near C5 a !ky l, Z1 is C2 alkylene, Z2 is absent, W is methylene, and R7 is H, then R5 and R6 are not Cx alkoxy.In some embodiments an LNP comprising Formula (xii) is used to deliver a TREM composition described herein to the liver and/or hepatocyte cells. (xi) In some embodiments an LNP comprising Formula (xi) is used to deliver a TREM composition described herein to the liver and/or hepatocyte cells.

.SR -x .--s JINN ־ Y ־־ x -־ ־ Rx ,- £ £ ( ' ( xii .... IH where R= v ־ 1 Q|i "'י 325 WO 2024/216206 PCT/US2024/024492 (xiv)In some embodiments an LNP comprises a compound of Formula (xiii) and a compound of Formul a (xi v) .OH .oh r" ' OH(xv)In some embodiments, an LNP comprising Formula (xv) is used to deliver a TREM composition described herein to the liver and/or hepatocyte cells.w ؛ C ° / •x(XV1)In some embodiments an LNP comprising a formulation of Formula (xvi) is used todeliver a TREM composition described herein to the lung endothelial cells. 326 WO 2024/216206 PCT/US2024/024492 In some embodiments, a lipid compound used to form lipid nanoparticles for the delivery of compositions described herein, e.g., a TREM described herein is made by one of the following reactions; H2N ... ■' + ■ (xx)(b) In some embodiments, a composition described herein (e.g., TREM composition) is provided in an LNP that comprises an ionizable lipid. In some embodiments, the ionizable lipid is heptadecan-9-yl 8-((2-hydroxyethyl)(6-oxo-6-(undecyloxy)hexyl)amino)octanoate (SM-102); e.g., as described in Example 1 of US9,867,888 (incorporated by reference herein in its entirety) 327 WO 2024/216206 PCT/US2024/024492 In some embodiments, the ionizable lipid is 9Z,12Z)-3-((4,4-bis(octyloxy)butanoyl)oxy)-2-((((3- (diethylamino)propoxy)carbonyl)oxy)methyl)propyl octadeca-9,12-dienoate (LP01), e.g., as synthesized in Example 13 of WO2015/095340 (incorporated by reference herein in its entirety). In some embodiments, the ionizable lipid is Di((Z)-non-2-en-l-yl) 9-((4-dimethylamino)- butanoyl)oxy)heptadecanedioate (L319), e.g. as synthesized in Example 7, 8, or 9 of US2012/0027803 (incorporated by reference herein in its entirety). In some embodiments, the ionizable lipid is l,r2))-2)-4)-2)) ־-(Bis(2-hydroxydodecyl)amino)ethyl)(2-hydroxy dodecyl) amino)ethyl)piperazin-l-yl)ethyl)azanediyl)bis(dodecan-2-ol) (C12-200), e.g., as synthesized in Examples 14 and 16 of WO2010/053572 (incorporated by reference herein in its entirety). In some embodiments, the ionizable lipid is Imidazole cholesterol ester (ICE) lipid (3S, 10R, 13R, 17R)-10, 13-dimethyl- 17- ((R)-6-methylheptan-2-yl)-2, 3, 4, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-lH- cyclopenta[a]phenanthren-3-yl 3-(lH-imidazol-4-yl)propanoate, e.g., Structure (I) from WO2020/106946 (incorporated by reference herein in its entirety).In some embodiments, an ionizable lipid may be a cationic lipid, an ionizable cationic lipid, e.g., a cationic lipid that can exist in a positively charged or neutral form depending on pH, or an amine-containing lipid that can be readily protonated. In some embodiments, the cationic lipid is a lipid capable of being positively charged, e.g., under physiological conditions. Exemplary cationic lipids include one or more amine group(s) which bear the positive charge. In some embodiments, the lipid particle comprises a cationic lipid in formulation with one or more of neutral lipids, ionizable amine-containing lipids, biodegradable alkyne lipids, steroids, phospholipids including polyunsaturated lipids, structural lipids (e.g., sterols), PEG, cholesterol and polymer conjugated lipids. In some embodiments, the cationic lipid may be an ionizable cationic lipid. An exemplary cationic lipid as disclosed herein may have an effective pKa over 6.0. In embodiments, a lipid nanoparticle may comprise a second cationic lipid having a different effective pKa (e.g., greater than the first effective pKa), than the first cationic lipid. A lipid nanoparticle may comprise between 40 and 60 mol percent of a cationic lipid, a neutral lipid, a steroid, a polymer conjugated lipid, and a therapeutic agent, e.g., a TREM described herein, encapsulated within or associated with the lipid nanoparticle. In some embodiments, the TREM is co-formulated with the cationic lipid. The TREM may be adsorbed to the surface of an LNP, e.g., an LNP comprising a cationic lipid. In some embodiments, the TREM may be encapsulated in an LNP, e.g., an LNP comprising a cationic lipid. In some embodiments, the lipid nanoparticle 328 WO 2024/216206 PCT/US2024/024492 may comprise a targeting moiety, e.g., coated with a targeting agent. In embodiments, the LNP formulation is biodegradable. In some embodiments, a lipid nanoparticle comprising one or more lipid described herein, e.g., Formula (i), (ii), (ii), (vii) and/or (ix) encapsulates at least 1%, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 92%, at least 95%, at least 97%, at least 98% or 100% of a TREM.Exemplary ionizable lipids that can be used in lipid nanoparticle formulations include, without limitation, those listed in Table 1 of WO2019051289, incorporated herein by reference. Additional exemplary lipids include, without limitation, one or more of the following formulae: X of US2016/0311759; I of US20150376115 or in US2016/0376224; I, II or III of US20160151284; I, IA, II, orllA of US20170210967; I-c of US20150140070; A of US2013/0178541; I of US2013/0303587 or US2013/0123338; I of US2015/0141678; II, III, IV, or V ofUS2015/0239926; I ofUS2017/0119904; I or II of WO2017/117528; A of US2012/0149894; A of US2015/00573 73; A of W02O13/116126; A of US2013/0090372; A of US2013/0274523; A of US2013/0274504; A of US2013/0053572; A of W02013/016058; A of W02012/162210; I of US2008/042973; 1, II, III, or IV of US2012/01287670; I or II of US2014/0200257; 1, II, or III of US2015/0203446; I or III of US2015/0005363; I, IA, IB, IC, ID, II, IIA, IB, IIC, IID, or III-XXIV of US2014/0308304; of US2013/0338210; I, II, III, or IV of W02009/132131; A of US2012/01011478; I or XXXV of US2012/0027796; XIV or XVII of US2012/0058144; of US2013/0323269; I of US2011/0117125; I, II, or III of US2011/0256175; I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII of US2012/0202871; 1, II, III, IV, V, VI, VII, VIII, X, XII, XIII, XIV, XV, or XVI of US2011/0076335; I or II of US2006/008378; I of US2013/0123338; I or X-A-Y-Z of US2015/0064242; XVI, XVII, or XVIII of US2013/0022649; 1, II, or III of US2013/0116307; 1, II, or III of US2013/0116307; I or II of US2010/0062967; I-X of US2013/0189351; I of US2014/0039032; V of US2018/0028664; I of US2016/0317458; I of US2013/0195920; 5, 6, or 10 of US10,221,127; 111-3 of WO2018/081480; 1-5 or 1-8 ofW02020/081938; 18 or 25 of US9,867,888; A of US2019/0136231; II of WO2020/219876; 1 of US2012/0027803; OF-02 of US2019/0240349; 23 of US 10,086,013; CKK-E12/A6 of Miao et al (2020); C12-200 of WO2010/053 572; 7C1 of Dahlman et al (2017); 304-013 or 503-013 of Whitehead et al; TS-P4C2 of US9,708,628; I of WO2020/106946; I of WO2020/106946. 329 WO 2024/216206 PCT/US2024/024492 In some embodiments, the ionizable lipid is MC3 (6Z,9Z,28Z,3 lZ)-heptatriaconta- 6,9,28,3 l-tetraen-19-yl-4-(dimethylamino) butanoate (DLin-MC3-DMA 0rMC3), e.g., as described in Example 9 of WO2019051289A9 (incorporated by reference herein in its entirety). In some embodiments, the ionizable lipid is the lipid ATX-002, e.g., as described in Example of WO2019051289A9 (incorporated by reference herein in its entirety). In some embodiments, the ionizable lipid is (13Z,16Z)-A,A-dimethyl-3- nonyldocosa-13,16-dien-l-amine (Compound 32), e.g., as described in Example 11 of WO2019051289A9 (incorporated by reference herein in its entirety). In some embodiments, the ionizable lipid is Compound 6 or Compound 22, e.g., as described in Example 12 of WO2019051289A9 (incorporated by reference herein in its entirety). Non-Cationic Lipids (e.g., Phospholipids)In some embodiments, the lipid-based carrier (or lipid nanoformulation) further comprises one or more non-cationic lipids. In some embodiments, the non-cationic lipid is a phospholipid. In some embodiments, the non-cationic lipid is a phospholipid substitute or replacement. In some embodiments, the non-cationic lipid is a negatively charged (anionic) lipid.Exemplary non-cationic lipids include, but are not limited to, di stearoyl-sn-glycero- phosphoethanolamine, distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), dioleoyl-phosphatidylethanolamine (DOPE), palmitoyloleoylphosphatidylcholine (POPC), palmitoyloleoylphosphatidylethanolamine (POPE), dioleoyl-phosphatidylethanolamine 4-(N-maleimidomethyl)-cyclohexane-l-carboxylate (DOPE- mal), dipalmitoyl phosphatidyl ethanolamine (DPPE), dimyristoylphosphoethanolamine (DMPE), distearoyl-phosphatidyl-ethanolamine (DSPE), monomethyl-phosphatidylethanolamine (such as 16-0-monomethyl PE), dimethyl- phosphatidylethanolamine (such as 16-O-dimethyl PE), 18-1-trans PE, 1-stearoyl-2-oleoyl-phosphatidyethanolamine (SOPE), hydrogenated soy phosphatidylcholine (HSPC), egg phosphatidylcholine (EPC), dioleoylphosphatidylserine (DOPS), sphingomyelin (SM), dimyristoyl phosphatidylcholine (DMPC), dimyristoyl phosphatidylglycerol (DMPG), distearoylphosphatidylglycerol (DSPG), dierucoylphosphatidylcholine (DEPC), palmitoyloleyolphosphatidylglycerol (POPG), dielaidoyl- phosphatidylethanolamine (DEPE), 1,2-dilauroyl- sn-glycero-3 -phosphocholine (DLPC), Sodium 1,2- ditetradecanoyl-sn-glycero-3-phosphate (DMPA), phosphatidylcholine (lecithin), 330 WO 2024/216206 PCT/US2024/024492 phosphatidylethanolamine, lysolecithin, lysophosphatidylethanolamine, phosphatidyl serine, phosphatidylinositol, sphingomyelin, egg sphingomyelin (ESM), phosphatidylethanolamine (cephalin), cardiolipin, phosphatidic acid, cerebrosides, dicetylphosphate, lysophosphatidylcholine, dilinoleoylphosphatidylcholine, or mixtures thereof. It is understood that other diacylphosphatidylcholine and diacylphosphatidylethanolamine phospholipids can also be used. The acyl groups in these lipids are preferably acyl groups derived from fatty acids having C10-C24 carbon chains, e.g., lauroyl, myristoyl, paimitoyl, stearoyl, or oleoyl. Additional exemplary lipids, in certain embodiments, include, without limitation, those described in Kim et al. (2020) dx.doi.org/10.1021/acs.nanolett.0c01386, which is incorporated herein by reference. Such lipids include, in some embodiments, plant lipids found to improve liver transfection with mRNA (e.g., DGTS).In some embodiments, the lipid-based carrier (or lipid nanoformulation) may comprise a combination of distearoylphosphatidylcholine/cholesterol, dipalmitoylphosphatidylcholine/cholesterol, dimyrystoylphosphatidylcholine/cholesterol, 1,2- Dioleoyl-sn-glycero-3-phosphocholine (DOPC)/cholesterol, or egg sphingomyelin/cholesterol.Other examples of suitable non-cationic lipids include, without limitation, nonphosphorous lipids such as, e.g., stearylamine, dodecylamine, hexadecylamine, acetyl palmitate, glycerol ricinoleate, hexadecyl stearate, isopropyl myristate, amphoteric acrylic polymers, triethanolamine-lauryl sulfate, alkyl-aryl sulfate polyethyloxylated fatty acid amides, dioctadecyl dimethyl ammonium bromide, ceramide, sphingomyelin, and the like. Other non- cationic lipids are described in WO 2017/099823 or US 2018/0028664, which are incorporated herein by reference in their entirety.In one embodiment, the lipid-based carrier (or lipid nanoformulation) further comprises one or more non-cationic lipid that is oleic acid or a compound of Formula 1, II, or IV of US 2018/0028664, which is incorporated herein by reference in its entirety.The non-cationic lipid content can be, for example, 0-30% (mol) of the total lipid components present. In some embodiments, the non-cationic lipid content is 5-20% (mol) or 10- 15% (mol) of the total lipid components present.In some embodiments, the lipid-based carrier (or lipid nanoformulation) further comprises a neutral lipid, and the molar ratio of an ionizable lipid to a neutral lipid ranges from about 2:1 to about 8:1 (e.g, about 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, or 8:1). 331 WO 2024/216206 PCT/US2024/024492 In some embodiments, the lipid-based carrier (or lipid nanoformulation) does not include any phospholipids.In some embodiments, the lipid-based carrier (or lipid nanoformulation) can further include one or more phospholipids, and optionally one or more additional molecules of similar molecular shape and dimensions having both a hydrophobic moiety and a hydrophilic moiety (e.g., cholesterol).Exemplary non-cationic lipids include, but are not limited to, di stearoyl-sn-glycero- phosphoethanolamine, distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), dioleoyl-phosphatidylethanolamine (DOPE), palmitoyloleoylphosphatidylcholine (POPC), palmitoyloleoylphosphatidylethanolamine (POPE), dioleoyl-phosphatidylethanolamine 4-(N-maleimidomethyl)-cyclohexane- 1 - carboxylate (DOPE-mal), dipalmitoyl phosphatidyl ethanolamine (DPPE), dimyristoylphosphoethanolamine (DMPE), distearoyl-phosphatidyl-ethanolamine (DSPE), monomethyl-phosphatidylethanolamine (such as 16-0-monomethyl PE), dimethyl- phosphatidylethanolamine (such as 16-O-dimethyl PE), 18-1-trans PE, l-stearoyl-2-oleoyl- phosphatidyethanolamine (SOPE), hydrogenated soy phosphatidylcholine (HSPC), egg phosphatidylcholine (EPC), dioleoylphosphatidylserine (DOPS), sphingomyelin (SM), dimyristoyl phosphatidylcholine (DMPC), dimyristoyl phosphatidylglycerol (DMPG), di stearoylphosphatidylglycerol (DSPG), dierucoylphosphatidylcholine (DEPC), palmitoyl 01 eyolphosphatidylglycerol (POPG), dielaidoyl- phosphatidylethanolamine (DEPE), lecithin, phosphatidylethanolamine, lysolecithin, lysophosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, egg sphingomyelin (ESM), cephalin, cardiolipin, phosphatidicacid,cerebrosides, dicetylphosphate, lysophosphatidylcholine, dilinoleoylphosphatidylcholine, or mixtures thereof. It is understood that other diacylphosphatidylcholine and diacylphosphatidylethanolamine phospholipids can also be used. The acyl groups in these lipids are preferably acyl groups derived from fatty acids having C10-C24 carbon chains, e.g., lauroyl, myristoyl, paimitoyl, stearoyl, or oleoyl. Additional exemplary lipids, in certain embodiments, include, without limitation, those described in Kim et al. (2020) dx.doi.org/10.1021/acs.nanolett.0c01386, incorporated herein by reference. Such lipids include, in some embodiments, plant lipids found to improve liver transfection with mRNA (e.g., DGTS). 332 WO 2024/216206 PCT/US2024/024492 Other examples of non-cationic lipids suitable for use in the lipid nanoparticles include, without limitation, nonphosphorous lipids such as, e.g., stearylamine, dodeeylamine, hexadecylamine, acetyl palmitate, glycerol ricinoleate, hexadecyl stereate, isopropyl myristate, amphoteric acrylic polymers, triethanolamine-lauryl sulfate, alkyl-aryl sulfate polyethyloxylated fatty acid amides, dioctadecyl dimethyl ammonium bromide, ceramide, sphingomyelin, and the like. Other non-cationic lipids are described in WO2017/099823 or US patent publication US2018/0028664, the contents of which is incorporated herein by reference in their entirety.In some embodiments, the non-cationic lipid is oleic acid or a compound of Formula 1, II, or IV of US2018/0028664, incorporated herein by reference in its entirety. The non-cationic lipid can comprise, for example, 0-30% (mol) of the total lipid present in the lipid nanoparticle. In some embodiments, the non-cationic lipid content is 5-20% (mol) or 10-15% (mol) of the total lipid present in the lipid nanoparticle. In embodiments, the molar ratio of ionizable lipid to the neutral lipid ranges from about2:l to about 8:1 (e.g., about 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, or 8:1).In some embodiments, the lipid nanoparticles do not comprise any phospholipids. Structural LipidsThe lipid-based carrier (or lipid nanoformulation) described herein may further comprise one or more structural lipids. As used herein, the term "structural lipid " refers to sterols (e.g, cholesterol) and also to lipids containing sterol moieties.Incorporation of structural lipids in the lipid nanoparticle may help mitigate aggregation of other lipid in the particle. Structural lipids can be selected from the group including but not limited to, cholesterol or cholesterol derivative, fecosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, tomatine, ursolic acid, alpha-tocopherol, hopanoids, phytosterols, steroids, and mixtures thereof. In some embodiments, the structural lipid is a sterol. In certain embodiments, the structural lipid is a steroid. In certain embodiments, the structural lipid is cholesterol. In certain embodiments, the structural lipid is an analog of cholesterol. In certain embodiments, the structural lipid is alpha-tocopherol.In some embodiments, structural lipids may be incorporated into the lipid-based carrier at molar ratios ranging from about 0.1 to 1.0 (cholesterol phospholipid).In some embodiments, sterols, when present, can include one or more of cholesterol or cholesterol derivatives, such as those described in WO 2009/127060 or US 2010/0130588, which are incorporated herein by reference in their entirety. Additional exemplary sterols include 333 WO 2024/216206 PCT/US2024/024492 phytosterols, including those described in Eygeris et al. (2020), Nano Lett. 2020;20(6):4543- 4549, incorporated herein by reference.In some embodiments, the structural lipid is a cholesterol derivative. Non-limiting examples of cholesterol derivatives include polar analogues such as 5a-cholestanol, 53- coprostanol, cholesteryl-(2 ’-hydroxy)-ethyl ether, cholesteryl-(40hydroxy)-butyl ether, and 6- ketocholestanol; non-polar analogues such as 5a-cholestane, cholestenone, 5a-cholestanone, 5p- cholestanone, and cholesteryl decanoate; and mixtures thereof. In some embodiments, the cholesterol derivative is a polar analogue, e.g., cholesteryl-(4Ehydroxy)-butyl ether. Exemplary cholesterol derivatives are described in WO 2009/127060 and US 2010/0130588, each of which is incorporated herein by reference in its entirety.In some embodiments, the lipid-based carrier (or lipid nanoformulation) further comprises sterol in an amount of 0-50 mol% (e.g, 0-10 mol %, 10-20 mol %, 20-50 mol%, 20- mol %, 30-40 mol %, or 40-50 mol %) of the total lipid components.In some aspects, the lipid nanoparticle can further comprise a component, such as a sterol, to provide membrane integrity. One exemplary sterol that can be used in the lipid nanoparticle is cholesterol and derivatives thereof. Non-limiting examples of cholesterol derivatives include polar analogues such as 5a-choiestanol, 53-coprostanol, choiesteryl-(2 ־- hydroxy)-ethyl ether, cholesteryl -(4’- hydroxy)-butyl ether, and 6-ketocholestanol; non-polar analogues such as 5a-cholestane, cholestenone, 5a-cholestanone, 5p-cholestanone, and cholesteryl decanoate; and mixtures thereof. In some embodiments, the cholesterol derivative is a polar analogue, e.g., choiesteryl-(4 ،-hydroxy)-butyl ether. Exemplary cholesterol derivatives are described in PCT publication W02009/127060 and US patent publication US2010/0130588, each of which is incorporated herein by reference in its entirety.In some embodiments, the component providing membrane integrity, such as a sterol, can comprise 0-50% (mol) (e.g., 0-10%, 10-20%, 20-30%, 30-40%, or 40-50%) of the total lipid present in the lipid nanoparticle. In some embodiments, such a component is 20-50% (mol) 30- 40% (mol) of the total lipid content of the lipid nanoparticle.Polymers and Polyethylene Glycol (PEG) - LipidsIn some embodiments, the lipid-based carrier (or lipid nanoformulation) may include one or more polymers or co-polymers, e.g, poly(lactic-co-glycolic acid) (PFAG) nanoparticles.In some embodiments, the lipid-based carrier (or lipid nanoformulation) may include one 334 WO 2024/216206 PCT/US2024/024492 or more polyethylene glycol (PEG) lipid. Examples of useful PEG-lipids include, but are not limited to, l,2-Diacyl-sn-Glycero-3- Phosphoethanolamine-N-[Methoxy(Poly ethylene glycol)- 350] (mPEG 350 PE); 1,2-Diacyl-sn- Glycero-3-Phosphoethanolamine-N- [Methoxy(Polyethylene glycol)-550] (mPEG 550 PE); 1,2- Diacyl-sn-Glycero-3- Phosphoethanolamine-N-[Methoxy(Polyethylene glycol)-750] (mPEG 750 PE); 1,2-Diacyl-sn- Glycero-3-Phosphoethanolamine-N-[Methoxy(Polyethylene glycol)- 1000] (mPEG 1000 PE); l,2-Diacyl-sn-Glycero-3-Phosphoethanolamine-N-[Methoxy(Polyethylene glycol)-2000] (mPEG 2000 PE); l,2-Diacyl-sn-Glycero-3-Phosphoethanolamine-N- [Methoxy(Polyethylene glycol)- 3000] (mPEG 3000 PE); l,2-Diacyl-sn-Glycero-3- Phosphoethanolamine-N- [Methoxy(Polyethylene glycol)-5000] (mPEG 5000 PE); N-Acyl- Sphingosine- 1- [Succinyl(Methoxy Polyethylene Glycol) 750] (mPEG 750 Ceramide); N-Acyl- Sphingosine- 1- [Succinyl(Methoxy Polyethylene Glycol) 2000] (mPEG 2000 Ceramide); and N- Acyl- Sphingosine-l-[Succinyl(Methoxy Polyethylene Glycol) 5000] (mPEG 5000 Ceramide). In some embodiments, the PEG lipid is a polyethyleneglycol-di acylglycerol (i.e., polyethyleneglycol diacylglycerol (PEG-DAG), PEG-cholesteroL or PEG-DMB) conjugate.In some embodiments, the lipid-based carrier (or nanoformulation) includes one or more conjugated Lipids (such as PEG-conjugated lipids or lipids conjugated to polymers described in Table 5 of WO 2019/217941, which is incorporated herein by reference in its entirety). In some embodiments, the one or more conjugated lipids is formulated with one or more ionic lipids (e.g., non-cationic lipid such as a neutral or anionic, or zwitterionic lipid); and one or more sterols (e.g., cholesterol).The PEG conjugate can comprise a PEG-dilaurylglycerol (Cl 2), a PEG- di my ri sty l glycerol (C14), a PEG-dipa1mitoylg1ycerol (Cl 6), a PEG-disteryl glycerol (C18), PEG- dilaurylglycamide (C12), PEG-dimyristylglycamide (Cl 4), PEG-dipalmitoylglycamide (Cl 6), and PEG-disterylglycamide (CIS).In some embodiments, conjugated lipids, when present, can include one or more of PEG- diacylglycerol (DAG) (such as l-(monomethoxy-polyethyleneglycol)-2,3- dimyristoylglycerol (PEG-DMG)), PEG-dialkyloxypropyl (DAA), PEG-phospholipid, PEG- ceramide (Cer), a pegylated phosphatidylethanoloamine (PEG-PE), PEG succinate diacylglycerol (PEGS-DAG) (such as 4-0-(2 p Edi(tetradecanoyloxy)propyl-l-0-(w- methoxy(poly ethoxy )ethyl) butanedioate (PEG-S-DMG)), PEG dialkoxypropylcarbam, N- (carbonyl-methoxypolyethylene glycol 2000)- 335 WO 2024/216206 PCT/US2024/024492 1 ,2-d1stearoyl-sn-glycero-3-phosphoethanolam1ne sodium salt, and those described in Table 2 of WO 2019/051289 (which is herein incorporated by reference in its entirety), and combinations of the foregoing.Additional exemplary PEG-lipid conjugates are described, for example, in US 5,885,613, US 6,287,591, US 2003/0077829, US 2003/0077829, US 2005/0175682, US 2008/0020058, US 2011/0117125, US 2010/0130588, US 2016/0376224, US 2017/0119904, US 2018/0028664, and WO 2017/099823, all of which are incorporated herein by reference in their entirety.In some embodiments, the PEG-lipid is a compound of Formula III, III-a-1, III-a-2, Ill-b- 1, III-b-2, or V of US 2018/0028664, which is incorporated herein by reference in its entirety. In some embodiments, the PEG-lipid is of Formula 11 of US 2015/0376115 or US 2016/0376224, both of which are incorporated herein by reference in their entirety. In some embodiments, the PEG-DAA conjugate can be, for example, PEG-dilauryloxypropyl, PEG- dimyristyloxypropyl, PEG-dipalmityloxypropyl, or PEG-distearyloxypropyl. In some embodiments, the PEG-lipid includes one of the following: In some embodiments, lipids conjugated with a molecule other than a PEG can also be used in place of PEG-lipid. For example, polyoxazoline (POZ)-lipid conjugates, polyamide-lipid conjugates (such as ATTA-lipid conjugates), and cationic-polymer lipid (GPL) conjugates can be used in place of or in addition to the PEG-lipid.Exemplary conjugated lipids, e.g., PEG-lipids, (POZ)-lipid conjugates, ATTA-lipid conjugates and cationic polymer-lipids, include those described in Table 2 of WO 336 WO 2024/216206 PCT/US2024/024492 2019/051289A9, which is incorporated herein by reference in its entirety.In some embodiments, the conjugated lipid (e.g., the PEGylated lipid) can be present in an amount of 0-20 mol% of the total lipid components present in the lipid-based carrier (or lipid nanoformulation). In some embodiments, the conjugated lipid (e.g., the PEGylated lipid) content is 0.5-10 mol% or 2-5 mol% of the total lipid components.When needed, the lipid-based carrier (or lipid nanoformulation) described herein may be coated with a polymer layer to enhance stability in vivo (e.g., sterically stabilized LNPs).Examples of suitable polymers include, but are not limited to, poly(ethylene glycol), which may form a hydrophilic surface layer that improves the circulation half-life of liposomes and enhances the amount of lipid nanoformulations (e.g., liposomes or LNPs) that reach therapeutic targets. See, e.g., Working et al. J Pharmacol Exp Ther, 289: 1128-1133 (1999); Gabizon et al., J Controlled Release 53: 275-279 (1998); Adi akha Hutch eon et al., Nat Biotechnol 17: 775-779 (1999); and Koning et al., Biochim Biophys Acta 1420: 153-167 (1999), which are incorporated herein by reference in their entirety.In some embodiments, the lipid nanoparticle can comprise a polyethylene glycol (PEG) or a conjugated lipid molecule. Generally, these are used to inhibit aggregation of lipid nanoparticles and/or provide steric stabilization. Exemplary conjugated lipids include, but are not limited to, PEG-lipid conjugates, polyoxazoline (POZ)-lipid conjugates, polyamide-lipid conjugates (such as ATTA-lipid conjugates), cationic-polymer lipid (CPL) conjugates, and mixtures thereof. In some embodiments, the conjugated lipid molecule is a PEG-lipid conjugate, for example, a (methoxy polyethylene glycol)-conjugated lipid.Exemplary PEG-lipid conjugates include, but are not limited to, PEG-diacylglycerol (DAG) (such as l-(monomethoxy-polyethyleneglycol)-2,3-dimyristoylglycerol (PEG-DMG)), PEG-dialkyloxypropyl (DAA), PEG-phospholipid, PEG-ceramide (Cer), a pegylated phosphatidylethanoloamine (PEG-PE), PEG succinate di acylglycerol (PEGS-DAG) (such as 4-0- (2’,3 ’-di(tetradecanoyloxy)propyl-l-0-(w-methoxy(polyethoxy)ethyl) butanedioate (PEG-S- DMG)), PEG dialkoxypropylcarbam, N-(carbonyl-methoxypolyethylene glycol 2000)-l,2- distearoyl-sn-glycero-3-phosphoethanolamine sodium salt, or a mixture thereof. Additional exemplary PEG-lipid conjugates are described, for example, in US5,885,613, US6,287,591, US2003/0077829, US2003/0077829, US2005/0175682, US2008/0020058, US2011/0117125, US2010/0130588, US2016/0376224, US2017/0119904, and US/099823, the contents of all of 337 WO 2024/216206 PCT/US2024/024492 which are incorporated herein by reference in their entirety. In some embodiments, a PEG-lipid is a compound of Formula III, III-a-I, III-a-2, ni-b-1, III-b-2, or V of US2018/0028664, the content of which is incorporated herein by reference in its entirety. In some embodiments, a PEG-lipid is of Formula II of US20150376115 or US2016/0376224, the content of both of which is incorporated herein by reference in its entirety. In some embodiments, the PEG-DAA conjugate can be, for example, PEG-di lauryl oxy propyl, PEG- dimyristyloxypropyl, PEG- dipalmityloxypropyl, or PEG-distearyloxypropyl. The PEG-lipid can be one or more of PEG- DMG, PEG-dilaurylglycerol, PEG-dipalmitoylglycerol, PEG- disterylglycerol, PEG- dilaurylglycamide, PEG-dimyristylglycamide, PEG- dipalmitoylglycamide, PEG- disterylglycamide, PEG-cholesterol (l-[8 ’-(Cholest-5-en-3[beta]- oxy)carboxamido-3 ’,6’- dioxaoctanyl] carbamoyl-[omega]-methyl-poly(ethylene glycol), PEG-DMB (3,4- Ditetradecoxylbenzyl- [omega]-methyl-poly(ethylene glycol) ether), and 1,2- dimyristoyl-sn- glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]. In some embodiments, the PEG-lipid comprises PEG-DMG, 1,2- dimyristoyl-sn-glycero-3-phosphoethanolamine-N- [methoxy(polyethylene glycol)-2000]. In some embodiments, the PEG-lipid comprises a structure selected from: In some embodiments, lipids conjugated with a molecule other than a PEG can also be used in place of PEG-lipid. For example, polyoxazoline (POZ)-lipid conjugates, polyamide-lipid conjugates (such as ATTA-lipid conjugates), and cationic-polymer lipid (GPL) conjugates can be used in place of or in addition to the PEG-lipid. 338 WO 2024/216206 PCT/US2024/024492 Exemplary conjugated lipids, i.e., PEG-lipids, (POZ)-lipid conjugates, ATTA-lipid conjugates and cationic polymer-lipids are described in the PCT and LIS patent applications listed in Table 2 of WO2019051289A9, the contents of all of which are incorporated herein by reference in their entirety.In some embodiments, the PEG or the conjugated lipid can comprise 0-20% (mol) of the total lipid present in the lipid nanoparticle. In some embodiments, PEG or the conjugated lipid content is 0.5- 10% or 2-5% (mol) of the total lipid present in the lipid nanoparticle. Molar ratios of the ionizable lipid, non-cationic-lipid, sterol, and PEG/conjugated lipid can be varied as needed. For example, the lipid particle can comprise 30-70% ionizable lipid by mole or by total weight of the composition, 0-60% cholesterol by mole or by total weight of the composition, 0- 30% non-cationic-lipid by mole or by total weight of the composition and 1-10% conjugated lipid by mole or by total weight of the composition. Preferably, the composition comprises 30- 40% ionizable lipid by mole or by total weight of the composition, 40-50% cholesterol by mole or by total weight of the composition, and 10- 20% non-cationic-lipid by mole or by total weight of the composition. In some other embodiments, the composition is 50-75% ionizable lipid by mole or by total weight of the composition, 20-40% cholesterol by mole or by total weight of the composition, and 5 to 10% non-cationic-lipid, by mole or by total weight of the composition and 1-10% conjugated lipid by mole or by total weight of the composition. The composition may contain 60-70% ionizable lipid by mole or by total weight of the composition, 25-35% cholesterol by mole or by total weight of the composition, and 5-10% non-cationic-lipid by mole or by total weight of the composition. The composition may also contain up to 90% ionizable lipid by mole or by total weight of the composition and 2 to 15% non-cationic lipid by mole or by total weight of the composition. The formulation may also be a lipid nanoparticle formulation, for example comprising 8-30% ionizable lipid by mole or by total weight of the composition, 5- 30% non- cationic lipid by mole or by total weight of the composition, and 0-20% cholesterol by mole or by total weight of the composition; 4-25% ionizable lipid by mole or by total weight of the composition, 4-25% non-cationic lipid by mole or by total weight of the composition, 2 to 25% cholesterol by mole or by total weight of the composition, 10 to 35% conjugate lipid by mole or by total weight of the composition, and 5% cholesterol by mole or by total weight of the composition; or 2-30% ionizable lipid by mole or by total weight of the composition, 2-30% non-cationic lipid by mole or by total weight of the composition, 1 to 15% cholesterol by mole or 339 WO 2024/216206 PCT/US2024/024492 by total weight of the composition, 2 to 35% conjugate lipid by mole or by total weight of the composition, and 1-20% cholesterol by mole or by total weight of the composition; or even up to 90% ionizable lipid by mole or by total weight of the composition and 2-10% non-cationic lipids by mole or by total weight of the composition, or even 100% cationic lipid by mole or by total weight of the composition. In some embodiments, the lipid particle formulation comprises ionizable lipid, phospholipid, cholesterol and a PEG-ylated lipid in a molar ratio of 50: 10:38.5: 1.5. In some other embodiments, the lipid particle formulation comprises ionizable lipid, cholesterol and a PEG-ylated lipid in a molar ratio of 60:38.5: 1.5.In some embodiments, the lipid particle comprises ionizable lipid, non-cationic lipid (e.g. phospholipid), a sterol (e.g., cholesterol) and a PEG-ylated lipid, where the molar ratio of lipids ranges from 20 to 70 mole percent for the ionizable lipid, with a target of 40-60, the mole percent of non-cationic lipid ranges from 0 to 30, with a target of 0 to 15, the mole percent of sterol ranges from 20 to 70, with a target of 30 to 50, and the mole percent of PEG-ylated lipid ranges from 1 to 6, with a target of 2 to 5.In some embodiments, the lipid particle comprises ionizable lipid / non-cationic- lipid / sterol / conjugated lipid at a molar ratio of 50; 10:38.5; 1.5.In an aspect, the disclosure provides a lipid nanoparticle formulation comprising phospholipids, lecithin, phosphatidylcholine and phosphatidylethanolamine.In some embodiments, one or more additional compounds can also be included. Those compounds can be administered separately, or the additional compounds can be included in the lipid nanoparticles of the invention. In other words, the lipid nanoparticles can contain other compounds in addition to the nucleic acid or at least a second nucleic acid, different than the first. Without limitations, other additional compounds can be selected from the group consisting of small or large organic or inorganic molecules, monosaccharides, disaccharides, trisaccharides, oligosaccharides, polysaccharides, peptides, proteins, peptide analogs and derivatives thereof, peptidomimetics, nucleic acids, nucleic acid analogs and derivatives, an extract made from biological materials, or any combinations thereof.In some embodiments, ENPs are directed to specific tissues by the addition of targeting domains. For example, biological ligands may be displayed on the surface of ENPs to enhance interaction with cells displaying cognate receptors, thus driving association with and cargo delivery to tissues wherein cells express the receptor. In some embodiments, the biological 340 WO 2024/216206 PCT/US2024/024492 ligand may be a ligand that drives delivery to the liver, e.g., LNPs that display GalNAc result in delivery of nucleic acid cargo to hepatocytes that display asialoglycoprotein receptor (ASGPR). The work of Akinc et al. Mol Ther 18(7): 1357-1364 (2010) teaches the conjugation of a trivalent GalNAc ligand to a PEG-lipid (GalNAc-PEG-DSG) to yield LNPs dependent on ASGPR for observable LNP cargo effect (see, e.g., FIG. 6 of Akinc et al. 2010, supra). Other ligand- displaying LNP formulations, e.g., incorporating folate, transferrin, or antibodies, are discussed in WO2017223135, which is incorporated herein by reference in its entirety, in addition to the references used therein, namely Kolhatkar et al., Curr Drug Discov Technol. 2011 8:197-206; Musacchio and Torchilin, Front Biosci. 2011 16:1388-1412; Yu et al., Mol MembrBiol. 2027:286-298; Patil et al., Crit Rev Ther Drug Carrier Syst. 2008 25:1-61 ; Benoit et al., Biomacromolecules. 2011 12:2708-2714; Zhao et al., Expert Opin Drug Deliv. 2008 5:309-319; Akinc et al., Mol Ther. 2010 18:1357-1364; Srinivasan et al., Methods Mol Biol. 2012 820:105- 116; Ben-Arie et al., Methods Mol Biol. 2012 757:497-507; Peer 2010 J Control Release. 20:63- 68; Peer et al., Proc Natl Acad Sci USA. 2007 104:4095-4100; Kim et al., Methods Mol Biol. 2011 721:339-353; Subramanya et al., Mol Ther. 2010 18:2028-2037; Song et al., Nat Biotechnol. 2005 23:709-717; Peer et al., Science. 2008 319:627-630; and Peer and Lieberman, Gene Ther. 2011 18:1127-1133.In some embodiments, LNPs are selected for tissue-specific activity by the addition of a Selective ORgan Targeting (SORT) molecule to a formulation comprising traditional components, such as ionizable cationic lipids, amphipathic phospholipids, cholesterol and poly(ethylene glycol) (PEG) lipids. The teachings of Cheng et al. Nat Nanotechnol 15(4):313- 320 (2020) demonstrate that the addition of a supplemental "SORT" component precisely alters the in vivo RNA delivery profile and mediates tissue-specific (e.g., lungs, liver, spleen) gene delivery and editing as a function of the percentage and biophysical property of the SORT molecule.In some embodiments, the LNPs comprise biodegradable, ionizable lipids. In some embodiments, the LNPs comprise (9Z,12Z)-3-((4,4-bis(octyloxy)butanoyl)oxy)-2-((((3- (diethylamino)propoxy)carbonyl)oxy)methyl)propyl octadeca-9,12-di enoate, also called 3- ((4,4- bis(octyloxy)butanoyl)oxy)-2-((((3-(diethylamino)propoxy)carbonyl)oxy)methyl)propyl (9Z,12Z)-octadeca-9,12-dienoate) or another ionizable lipid. See, e.g, lipids of WO2019/067992, WO/2017/173054, WO2015/095340, and WO2014/136086, as well as references provided 341 WO 2024/216206 PCT/US2024/024492 therein. In some embodiments, the term cationic and ionizable in the context of LNP lipids is interchangeable, e.g., wherein ionizable lipids are cationic depending on the pH.In some embodiments, the average LNP diameter of the LNP formulation may be between 10s of nm and 100s of nm, e.g., measured by dynamic light scattering (DLS). In some embodiments, the average LNP diameter of the LNP formulation may be from about 40 nm to about 150 nm, such as about 40 nm, 45 nm, 50 nm, 55 nm, 60 nm, 65 nm, 70 nm, 75 nm, 80 nm, nm, 90 nm, 95 nm, 100 nm, 105 nm, 110 nm, 115 nm, 120 nm, 125 nm, 130 nm, 135 nm, 1nm, 145 nm, or 150 nm. In some embodiments, the average LNP diameter of the LNP formulation may be from about 50 nm to about 100 nm, from about 50 nm to about 90 nm, from about 50 nm to about 80 nm, from about 50 nm to about 70 nm, from about 50 nm to about nm, from about 60 nm to about 100 nm, from about 60 nm to about 90 nm, from about 60 nm to about 80 nm, from about 60 nm to about 70 nm, from about 70 nm to about 100 nm, from about nm to about 90 nm, from about 70 nm to about 80 nm, from about 80 nm to about 100 nm, from about 80 nm to about 90 nm, or from about 90 nm to about 100 nm. In some embodiments, the average LNP diameter of the LNP formulation may be from about 70 nm to about 100 nm. In a particular embodiment, the average LNP diameter of the LNP formulation may be about nm. In some embodiments, the average LNP diameter of the LNP formulation may be about 1nm. In some embodiments, the average LNP diameter of the LNP formulation ranges from about 1 mm to about 500 mm, from about 5 mm to about 200 mm, from about 10 mm to about 100 mm, from about 20 mm to about 80 mm, from about 25 mm to about 60 mm, from about mm to about 55 mm, from about 35 mm to about 50 mm, or from about 38 mm to about 42 mm.A LNP may, in some instances, be relatively homogenous. A poly dispersity index may be used to indicate the homogeneity of a LNP, e.g., the particle size distribution of the lipid nanoparticles. A small (e.g., less than 0.3) polydispersity index generally indicates a narrow particle size distribution. A LNP may have a poly dispersity index from about 0 to about 0.25, such as 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, or 0.25. In some embodiments, the poly dispersity index of a LNP may be from about 0.10 to about 0.20.The zeta potential of a LNP may be used to indicate the electrokinetic potential of the composition. In some embodiments, the zeta potential may describe the surface charge of an LNP Lipid nanoparticles with relatively low charges, positive or negative, are generally 342 WO 2024/216206 PCT/US2024/024492 desirable, as more highly charged species may interact undesirably with cells, tissues, and other elements in the body. In some embodiments, the zeta potential of a LNP may be from about -mV to about +20 mV, from about -10 mV to about +15 mV, from about -10 mV to about +mV, from about -10 mV to about +5 mV, from about -10 mV to about 0 mV, from about -10 mV to about -5 mV, from about -5 mV to about +20 mV, from about -5 mV to about +15 mV, from about -5 mV to about +10 mV, from about -5 mV to about +5 mV, from about -5 mV to about mV, from about 0 mV to about +20 mV, from about 0 mV to about +15 mV, from about 0 mV to about +10 mV, from about 0 mV to about +5 mV, from about +5 mV to about +20 mV, from about +5 mV to about +15 mV, or from about +5 mV to about +10 mV.The efficiency of encapsulation of a TREM describes the amount of TREM that is encapsulated or otherwise associated with a LNP after preparation, relative to the initial amount provided. The encapsulation efficiency is desirably high (e.g., close to 100%). The encapsulation efficiency may be measured, for example, by comparing the amount of TREM in a solution containing the lipid nanoparticle before and after breaking up the lipid nanoparticle with one or more organic solvents or detergents. An anion exchange resin may be used to measure the amount of free protein or nucleic acid (e.g., RNA) in a solution. Fluorescence may be used to measure the amount of free TREM in a solution. For the lipid nanoparticles described herein, the encapsulation efficiency of a TREM may be at least 50%, for example 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%. In some embodiments, the encapsulation efficiency may be at least 80%. In some embodiments, the encapsulation efficiency may be at least 90%. In some embodiments, the encapsulation efficiency may be at least 95%.A LNP may optionally comprise one or more coatings. In some embodiments, a LNP may be formulated in a capsule, film, or table having a coating. A capsule, film, or tablet including a composition described herein may have any useful size, tensile strength, hardness or density.Additional exemplary lipids, formulations, methods, and characterization of LNPs are taught by WO2020061457, which is incorporated herein by reference in its entirety.In some embodiments, in vitro or ex vivo cell lipofections are performed using Lipofectamine MessengerMax (Thermo Fisher) or TransIT-mRNA Transfection Reagent (Mirus Bio). In certain embodiments, LNPs are formulated using the GenVoy_ILM ionizable lipid mix 343 WO 2024/216206 PCT/US2024/024492 (Precision NanoSystems). In certain embodiments, LNPs are formulated using 2,2-dilinoleyl-4- dimethylaminoethyl-[!,3]-dioxolane (DLin-KC2-DMA) or dilinoleylmethyl-4- dimethylaminobutyrate (DLin-MC3-DMA or MC3), the formulation and in vivo use of which are taught in Jayaraman et al. Angew Chem Int Ed Engl 51(34):8529-8533 (2012), incorporated herein by reference in its entirety.LNP formulations optimized for the delivery of CRISPR-Cas systems, e.g., Cas9-gRNA RNP, gRNA, Cas9 mRNA, are described in WO2019067992 and WO2019067910, both incorporated by reference.Additional specific LNP formulations useful for delivery of nucleic acids are described in US8158601 and US8168775, both incorporated by reference, which include formulations used in patisiran, sold under the name ONPATTRO.Exosomes can also be used as drug delivery vehicles for the TREM, TREM core fragment, TREM fragment, or TREM compositions or pharmaceutical TREM composition described herein. For a review, see Ha et al. July 2016. Acta Pharmaceutica Sinica B. Volume 6, Issue 4, Pages 287-296; https://doi.Org/10.1016/j.apsb.2016.02.001 .Ex vivo differentiated red blood cells can also be used as a carrier for a TREM, TREM core fragment, TREM fragment, or TREM composition, or pharmaceutical TREM composition described herein. See, e.g., WO2015073587; WO2017123646; WO2017123644;WO2018102740; wO2016183482; WO2015153102; WO2018151829; WO2018009838; Shi et al. 2014. Proc Natl Acad Sci USA. 111(28): 10131-10136; US Patent 9,644,180; Huang et al. 2017. Nature Communications 8; 423; Shi et al. 2014. Proc Natl Acad Sci USA. 111(28): 10131-10136.Fusosome compositions, e.g., as described in WO2018208728, can also be used as carriers to deliver the TREM, TREM core fragment, TREM fragment, or TREM composition, or pharmaceutical TREM composition described herein.Virosomes and virus-like particles (VLPs) can also be used as carriers to deliver a TREM, TREM core fragment, TREM fragment, or TREM composition, or pharmaceutical TREM composition described herein to targeted cells.Plant nanovesicles, e.g., as described in WO2011097480A1, WO2013070324A1, or WO2017004526A1 can also be used as carriers to deliver the TREM, TREM core fragment, 344 WO 2024/216206 PCT/US2024/024492 TREM fragment, or TREM composition, or pharmaceutical TREM composition described herein.Percentages of Lipid Nanoformulation ComponentsIn some embodiments, the lipid-based carrier (or lipid nanoformulation) comprises one of more of the compounds described herein, optionally a non-cationic lipid (e.g., a phospholipid), a sterol, a neutral lipid, and optionally conjugated lipid (e.g., a PEGylated lipid) that inhibits aggregation of particles. In some embodiments, the lipid-based carrier (or lipid nanoformulation) further comprises a TREM (e.g., a TREM described herein). The amounts of these components can be varied independently and to achieve desired properties. For example, in some embodiments, the ionizable lipid including the lipid compounds described herein is present in an amount from about 20 mol % to about 100 mol% (e.g., 20-90 mol%, 20-80 mol%, 20-70 mol%, 25-100 mol%, 30-70 mol%, 30-60 mol%, 30-40 mol%, 40-50 mol%, or 50-mol%) of the total lipid components; a non-cationic lipid (e.g, phospholipid) is present in an amount from about 0 mol% to about 50 mol% (e.g., 0-40 mol%, 0-30 mol%, 5-50 mol%, 5-mol%, 5-30 mol%, or 5-10 mol%) of the total lipid components, a conjugated lipid (e.g., a PEGylated lipid) in an amount from about 0.5 mol% to about 20 mol% (e.g., 1-10 mol% or 5- 10%) of the total lipid components, and a sterol in an amount from about 0 mol % to about mol% (e.g., 0-50 mol%, 10-60 mol%, 10-50 mol%, 15-60 mol%, 15-50 mol%, 20-50 mol%, 20- mol%) of the total lipid components, provided that the total mol% of the lipid component does not exceed 100%.In some embodiments, the lipid-based carrier (or lipid nanoformulation) comprises about 25-100 mol% of the ionizable lipid including the lipid compounds described herein, about 0-mol% phospholipid, about 0-50 mol% sterol, and about 0-10 mol% PEGylated lipid.In some embodiments, the lipid-based carrier comprises a TREM (e.g., a TREM described herein) that is formulated in a lipid nanoparticle, wherein the lipid nanoparticle comprises about 25-100 mol% of the ionizable lipid including the lipid compounds described herein, about 0-50 mol% phospholipid, about 0-50 mol% sterol, and about 0-10 mol% PEGylated lipid. In some embodiments, the encapsulation efficiency of the payload may be at least 70%.In one embodiment, the lipid-based carrier (or lipid nanoformulation) comprises about 25-100 mol% of the ionizable lipid including the lipid compounds described herein; about 0- 345 WO 2024/216206 PCT/US2024/024492 mol% phospholipid (e.g., DSPC), about 0-50 mol% sterol (e.g., cholesterol), and about 0-mol% PEGylated lipid.In some embodiments, the lipid-based carrier comprises a TREM (e.g., a TREM described herein) that is formulated in a lipid nanoparticle, wherein the lipid nanoparticle comprises about 25-100 mol% of the ionizable lipid including the lipid compounds described herein; about 0-40 mol% phospholipid (e.g., DSPC), about 0-50 mol% sterol (e.g., cholesterol), and about 0-10 mol% PEGylated lipid. In some embodiments, the encapsulation efficiency of the payload may be at least 70%.In some embodiments, the lipid-based carrier (or lipid nanoformulation) comprises about 30-60 mol% (e.g., about 35-55 mol%, or about 40-50 mol%) of the ionizable lipid including the lipid compounds described herein, about 0-30 mol% (e.g, 5-25 mol%, or 10-20 mol%) phospholipid, about 15-50 mol% (e.g., 18.5-48.5 mol%, or 30-40 mol%) sterol, and about 0-mol% (e.g., 1-5 mol%, or 1.5-2.5 mol%) PEGylated lipid.In some embodiments, the lipid-based carrier comprises a TREM (e.g., a TREM described herein) that is formulated in a lipid nanoparticle, wherein the lipid nanoparticle comprises about 30-60 mol% (e.g., about 35-55 mol%, or about 40-50 mol%) of the ionizable lipid including the lipid compounds described herein, about 0-30 mol% (e.g., 5-25 mol%, or 10- mol%) phospholipid, about 15-50 mol% (e.g., 18.5-48.5 mol%, or 30-40 mol%) sterol, and about 0-10 mol% (e.g., 1-5 mol%, or 1.5-2.5 mol%) PEGylated lipid. In some embodiments, the encapsulation efficiency of the payload may be at least 70%.In some embodiments, molar ratios of ionizable lipid/sterol/phospholipid (or another structural lipid)/PEG-lipid/additional components is varied in the following ranges: ionizable lipid (25-100%); phospholipid (DSPC) (0-40%); sterol (0-50%); and PEG lipid (0-5%).In some embodiments, the lipid-based carrier comprises a TREM (e.g., a TREM described herein) that is formulated in a lipid nanoparticle, wherein the lipid nanoparticle comprises molar ratios of ionizable lipid/sterol/phospholipid (or another structural lipid)/PEG- lipid/additional components in the following ranges: ionizable lipid (25-100%); phospholipid (DSPC) (0-40%); sterol (0-50%); and PEG lipid (0-5%). In some embodiments, the encapsulation efficiency of the payload may be at least 70%.In some embodiments, the lipid-based carrier (or lipid nanoformulation) comprises, by mol% or wt% of the total lipid components, 50-75% ionizable lipid (including the lipid 346 WO 2024/216206 PCT/US2024/024492 compound as described herein), 20-40% sterol (e.g, cholesterol or derivative), 0 to 10% non- cationic-lipid, and 1-10% conjugated lipid (e.g., the PEGylated lipid).In some embodiments, the lipid-based carrier comprises a TREM (e.g., a TREM described herein) that is formulated in a lipid nanoparticle, wherein the lipid nanoparticle comprises, by mol% or wt% of the total lipid components, 50-75% ionizable lipid (including the lipid compound as described herein), 20-40% sterol (e.g, cholesterol or derivative), 0 to 10% non-cationic-lipid, and 1-10% conjugated lipid (e.g, the PEGylated lipid). In some embodiments, the encapsulation efficiency of the payload may be at least 70%.In some embodiments, the lipid-based carrier (or lipid nanoformulation) comprises (i) a TREM (e.g., a TREM described herein); (ii) a cationic lipid comprising from 50 mol% to mol% of the total lipid present in the lipid-based carrier; (iii) a non-cationic lipid comprising a mixture of a phospholipid and a cholesterol derivative thereof, wherein the phospholipid comprises from 3 mol% to 15 mol% of the total lipid present in the lipid-based carrier and the cholesterol or derivative thereof comprises from 30 mol% to 40 mol% of the total lipid present in the lipid-based carrier; and (iv) a conjugated lipid comprising 0.5 mol% to 2 mol% of the total lipid present in the particle.In some embodiments, the lipid-based carrier (or lipid nanoformulation) comprises (i) a TREM (e.g., a TREM described herein); (ii) a cationic lipid comprising from 50 mol % to mol % of the total lipid present in the lipid-based carrier; (iii) a non-cationic lipid comprising from 13 mol % to 49.5 mol % of the total lipid present in the lipid-based carrier; and (d) a conjugated lipid comprising from 0.5 mol % to 2 mol % of the total lipid present in the lipid- based carrier.In some embodiments, the phospholipid component in the mixture may be present from mol% to 20 mol%, from 2 mol% to 15 mol%, from 2 mol% to 12 mol%, from 4 mol% to mol%, from 4 mol% to 10 mol%, from 5 mol % to 10 mol%, (or any fraction of these ranges) of the total lipid components. In some embodiments, the lipid-based carrier (or lipid nanoformulation) is phospholipid-free.In some embodiments, the sterol component (e.g. cholesterol or derivative) in the mixture may comprise from 25 mol% to 45 mol%, from 25 mol% to 40 mol%, from 25 mol% to mol%, from 25 mol% to 30 mol%, from 30 mol% to 45 mol%, from 30 mol% to 40 mol%, from mol % to 35 mol%, from 35 mol% to 40 mol%, from 27 mol% to 37 mol%, or from 27 mol % 347 WO 2024/216206 PCT/US2024/024492 to 35 mol% (or any fraction of these ranges) of the total lipid components.In some embodiments, the non-ionizable lipid components in the lipid-based carrier (or lipid nanoformulation) may be present from 5 mol% to 90 mol%, from 10 mol% to 85 mol%, or from 20 mol% to 80 mol% (or any fraction of these ranges) of the total lipid components.The ratio of total lipid components to the payload (e.g, an encapsulated therapeutic agent such as a TREM (e.g., a TREM described herein) can be varied as desired. For example, the total lipid components to the payload (mass or weight) ratio can be from about 10:1 to about 30:1. In some embodiments, the total lipid components to the payload ratio (mass/mass ratio; w/w ratio) can be in the range of from about 1:1 to about 25:1, from about 10:1 to about 14:1, from about 3:1 to about 15:1, from about 4:1 to about 10:1, from about 5:1 to about 9:1, or about 6:1 to about 9:1. The amounts of total lipid components and the payload can be adjusted to provide a desired N/P ratio, for example, N/P ratio of 3, 4, 5,6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or higher. Generally, the lipid-based carrier (or lipid nanoformulation ’s) overall lipid content can range from about 5 mg/ml to about mg/mL. Nitrogen :phosphate ratios (N:P ratio) is evaluated at values between 0.1 and 100.The efficiency of encapsulation of a payload such as a protein and/or nucleic acid, describes the amount of protein and/or nucleic acid that is encapsulated or otherwise associated with a lipid nanoformulation (e.g., liposome or LNP) after preparation, relative to the initial amount provided. The encapsulation efficiency is desirably high (e.g., at least 70%. 80%. 90%. 95%, close to 100%). The encapsulation efficiency may be measured, for example, by comparing the amount of protein or nucleic acid in a solution containing the liposome or LNP before and after breaking up the liposome or LNP with one or more organic solvents or detergents. An anion exchange resin may be used to measure the amount of free protein or nucleic acid (e.g., RNA) in a solution. Fluorescence may be used to measure the amount of free protein and/or nucleic acid (e.g., RNA) in a solution. For the lipid-based carrier (or lipid nanoformulation) described herein, the encapsulation efficiency of a protein and/or nucleic acid may be at least 50%, for example 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%. In some embodiments, the encapsulation efficiency may be at least 70%. In some embodiments, the encapsulation efficiency may be at least 80%. In some embodiments, the encapsulation efficiency may be at least 90%. In some embodiments, the encapsulation efficiency may be at least 95%. 348 WO 2024/216206 PCT/US2024/024492 Delivery without a carrierA TREM, a TREM core fragment or a TREM fragment, a TREM composition or a pharmaceutical TREM composition described herein can be administered to a cell without a carrier, e.g., via naked delivery of the TREM, a TREM core fragment or a TREM fragment, a TREM composition or a pharmaceutical TREM composition.In some embodiments, naked delivery as used herein refers to delivery without a carrier. In some embodiments, delivery without a carrier, e.g., naked delivery, comprises delivery with a moiety, e.g., a targeting peptide.In some embodiments, a TREM, a TREM core fragment or a TREM fragment, or TREM composition, or pharmaceutical TREM composition described herein is delivered to a cell without a carrier, e.g., via naked delivery. In some embodiments, the delivery without a carrier, e.g., naked delivery, comprises delivery with a moiety, e.g., a targeting peptide.

Use of TREMs A TREM composition (e.g., a pharmaceutical TREM composition described herein) can modulate a function in a cell, tissue or subject. In embodiments, a TREM composition (e.g., a pharmaceutical TREM composition) described herein is contacted with a cell or tissue, or administered to a subject in need thereof, in an amount and for a time sufficient to modulate (increase or decrease) one or more of the following parameters: adaptor function (e.g., cognate or non-cognate adaptor function), e.g., the rate, efficiency, robustness, and/or specificity of initiation or elongation of a polypeptide chain; ribosome binding and/or occupancy; regulatory function (e.g., gene silencing or signaling); cell fate; mRNA stability; protein stability; protein transduction; protein compartmentalization. A parameter may be modulated, e.g., by at least 5% (e.g, at least 10%, 15%, 20%, 25%, 30%, 40%. 50%. 60%. 70%, 80%, 90%, 100%, 150%, 200% or more) compared to a reference tissue, cell or subject (e.g., a healthy, wild-type or control cell, tissue or subject).All references and publications cited herein are hereby incorporated by reference.The following examples are provided to further illustrate some embodiments of the present invention, but are not intended to limit the scope of the invention; it will be understood by their exemplary nature that other procedures, methodologies, or techniques known to those skilled in the art may alternatively be used. 349 WO 2024/216206 PCT/US2024/024492 ENUMERATED EMBODIMENTS1. A tRNA effector molecule (TREM) comprising a sequence of Formula (1):[Ll]x-[ASt Domainl]-[L2]x-[DH Domain]-[L3]x-[ACH Domain] -[VL Domain]-[TH Domain]-[L4]x-[ASt Domain2]-[L5]x (1), wherein:independently, [Li] and [VL Domain], are optional;x is 0 or 1; andthe TREM comprises a nucleotide substitution (e.g., a nucleotide mutation) in the TREM capable of modulating a functional parameter of the TREM. 2. The TREM of embodiment 1, wherein the functional parameter is activity of the TREM or stability of the TREM 3. The TREM of any one of the preceding embodiments, wherein the functional parameter comprises premature termination codon (PTC) readthrough activity of the TREM (e.g., an increased level of PTC readthrough activity or decreased PTC readthrough activity), e.g., in a sample (e.g., a cell) or in a subject. 4. The TREM of any one of the preceding embodiments, wherein the functional parameter comprises stability of the TREM (e.g., increased stability of the TREM or decreased stability of the TREM), e.g., in a sample (e.g., a cell) or in a subject.

. The TREM of any one of the preceding embodiments, wherein the functional parameter is selected from:(a) protein translation;(b) expression level (e.g., of polypeptide or protein, or mRNA);(c) post-translational modification of polypeptide or protein;(d) folding (e.g, of polypeptide or protein, or mRNA),(e) structure (e.g., of polypeptide or protein, or mRNA),(f) transduction (e.g., of polypeptide or protein),(g) compartmentalization (e.g., of polypeptide or protein, or mRNA), 350 WO 2024/216206 PCT/US2024/024492 (h) incorporation (e.g., of polypeptide or protein, or mRNA) into a supermolecular structure, e.g., incorporation into a membrane, proteasome, or ribosome,(i) incorporation into a multimeric polypeptide, e.g., a homo or heterodimer, and/or(j) stability. 6. The TREM of embodiment 5, wherein the functional parameter further comprises:(1) modulation of a signaling pathway, e.g., a cellular signaling pathway which is downstream or upstream of the protein encoded by the endogenous ORF having a first sequence or PTC;(2) cell fate modulation;(3) ribosome occupancy modulation;(4) protein translation modulation;(5) mRNA stability modulation;(6) protein folding and structure modulation;(7) protein transduction or compartmentalization modulation; and/or(8) protein stability modulation. 7. The TREM of any one of the preceding embodiments, wherein the TREM comprises a TREM having at least 70%, 75%, 80%, 85%, 90%, 95%, or 99% sequence identity with a TREM provided in FIGs. 3 or 23. 8. The TREM of any one of the preceding embodiments, wherein the TREM comprises a nucleotide sequence that differs by 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or nucleotides from the nucleotide sequence of a TREM provided in FIGs. 3 or 23. 9. The TREM of any one of the preceding embodiments, wherein the TREM comprises a nucleotide sequence that differs by 10, 15, 20, 25, 30, 35 or 40 nucleotides from the nucleotide sequence of a TREM provided in FIGs. 3 or 23. 351 WO 2024/216206 PCT/US2024/024492 . The TREM of any one of the preceding embodiments, wherein the TREM comprises a nucleotide sequence that differs by more than 5 nucleotides from the nucleotide sequence of a TREM provided in FIGs. 3 or 23. 11. The TREM of any one of the preceding embodiments, wherein the TREM comprises a nucleotide sequence that differs by more than 10 nucleotides from the nucleotide sequence of a TREM provided in FIGs. 3 or 23. 12. The TREM of any one of the preceding embodiments, wherein the TREM comprises a sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides from the nucleotide sequence of a TREM provided in FIGs. 3 or 23. 13. The TREM of any one of the preceding embodiments, wherein the TREM comprises a nucleotide sequence that differs by no more than 10, 15, 20, 25, 30, 35 or 40 nucleotides from the nucleotide sequence of a TREM provided in FIGs. 3 or 23. 14. The TREM of any one of the preceding embodiments, wherein the TREM comprises a nucleotide sequence that differs by no more than 1 nucleotide from the nucleotide sequence of a TREM provided in FIGs. 3 or 23.

. The TREM of any one of the preceding embodiments, wherein the TREM comprises a nucleotide sequence that differs by no more than 5 nucleotides from the nucleotide sequence of a TREM provided in FIGs. 3 or 23. 16. The TREM of any one of the preceding embodiments, wherein the TREM comprises a nucleotide sequence that differs by no more than 10 nucleotides from the nucleotide sequence of a TREM provided in FIGs. 3 or 23. 17. The TREM of any one of the preceding embodiments, wherein the TREM comprises a nucleotide substitution within the [ASt Domainl], e.g., the nucleotide substitution is at any of positions 1, 2, 3, 4, 5, 6, 7, 8, or 9 within the [ASt Domainl], 352 WO 2024/216206 PCT/US2024/024492 18. The TREM of any one of the preceding embodiments, wherein the TREM comprises a nucleotide substitution within the [DH Domain], e.g., the nucleotide substitution is at any of positions 1, 2, 3, 4, 5, 6, 7, 8, or 9 within the [DH Domain], 19. The TREM of any one of the preceding embodiments, wherein the TREM comprises a nucleotide substitution within the [ACH Domain], e.g., the nucleotide substitution is at any of positions 1, 2, 3, 4, 5, 6, 7, 8, or 9 within the [ACH Domain], . The TREM of any one of the preceding embodiments, wherein the TREM comprises a nucleotide substitution within the [VL Domain], e.g., the nucleotide substitution is at any of positions 1, 2, 3, 4, 5, 6, 7, 8, or 9 within the [VL Domain], 21. The TREM of any one of the preceding embodiments, wherein the TREM comprises a nucleotide substitution within the [TH Domain], e.g., the nucleotide substitution is at any of positions 1, 2, 3, 4, 5, 6, 7, 8, or 9 within the [TH Domain], 22. The TREM of any one of the preceding embodiments, wherein the TREM comprises a nucleotide substitution within the [ASt Domain2], e.g., the nucleotide substitution is at any of positions 1, 2, 3, 4, 5, 6, 7, 8, or 9 within the [ASt Domain2], 23. The TREM of any one of the preceding embodiments, wherein the TREM comprises a nucleotide substitution within the [DH Domain], e.g., the nucleotide substitution is at any of positions 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26 within the [DH Domain]. 24. The TREM of any one of the preceding embodiments, wherein the TREM comprises a nucleotide substitution within the [ACH Domain], e.g., the nucleotide substitution is at any of positions 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, or 43 within the [ACH Domain]. 353 WO 2024/216206 PCT/US2024/024492 . The TREM of any one of the preceding embodiments, wherein the TREM comprises a nucleotide substitution within the [VL Domain], e.g., the nucleotide substitution is at any of positions 44, 45, 46, 47, 48, or 49 within the [VL Domain], 26. The TREM of any one of the preceding embodiments, wherein the TREM comprises a nucleotide substitution within the [TH Domain], e.g., the nucleotide substitution is at any of positions 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, or 64 within the [TH Domain], 27. The TREM of any one of the preceding embodiments, wherein the TREM comprises a nucleotide substitution within the [ASt Domain2], e.g., the nucleotide substitution is at any of positions 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, or 76 within the [ASt Domain2]. 28. The TREM of any one of the preceding embodiments, wherein the TREM has a sequence selected from a sequence provided in FIGs. 3 or 23. 29. The TREM of any one of the preceding embodiments, wherein the TREM comprises a plurality of nucleotide substitutions.

. The TREM of any one of any one of the preceding embodiments, wherein the nucleotide substitution comprises substituting a first naturally occurring nucleotide with an adenosine, guanosine, cytosine, or uracil nucleotide. 31. The TREM of any one of the preceding embodiments, wherein the TREM is selected from SEQIDNOs. 625-700, 701-800, 801-900, 901-1000, 1001-1100, 1101-1151, 1290-1300, 1301-1400, or 1401-1456 in FIG. 3. 32. The TREM of any one of the preceding embodiments, wherein the TREM is selected from SEQIDNOs: 1457-1500, 1501-1600, 1601-1700, 1701-1800, 1801-1900, 1901-2000, or 2001-2032 in FIG. 23. 354 WO 2024/216206 PCT/US2024/024492 33. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution does not exhibit a difference in a functional parameter from a TREM in FIGs. 3 or 23. 34. The TREM of any one of embodiments 1-26, wherein the TREM comprising a nucleotide substitution exhibits a difference in a functional parameter from a TREM in FIGs. 3 or 23.

. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution exhibits an improvement in a functional parameter from a TREM in FIGs. or 23. 36. The TREM of any one of the preceding embodiments, wherein the improvement comprises an improvement of about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%. 45%, 50%. 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or greater, e.g., compared with the functional parameter of a TREM provided in FIGs. 3 or 23. 37. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution exhibits a reduction in a functional parameter from a TREM in FIGs. 3 or 23. 38. The TREM of any one of the preceding embodiments, wherein the reduction comprises a reduction of about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%. 45%, 50%. 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or greater, e.g., compared with the functional parameter of a TREM provided in FIGs. 3 or 23. 39. The TREM of any one of the preceding embodiments, wherein the TREM comprises a nucleotide substitution at any of positions 1, 2, 3, 4, 5, 6, or 7, e.g., within the [ASt Domainl].40. The TREM of any one of the preceding embodiments, wherein the TREM comprises a nucleotide substitution at any of positions 16, 17, or 20a, e.g., within the [DH Domain], 355 WO 2024/216206 PCT/US2024/024492 41. The TREM of any one of the preceding embodiments, wherein the TREM comprises a nucleotide substitution at any of positions 27, 28, 29, 30, 31, 39, 40, 41, 42, or 43, e.g., within the [ACH Domain]. 42. The TREM of any one of the preceding embodiments, wherein the TREM comprises a nucleotide substitution at any of positions 51, 59, 60, or 63, e.g., within the [TEI Domain], 43. The TREM of any one of the preceding embodiments, wherein the TREM comprises a nucleotide substitution at any of positions 66, 67, 68, 69, 70, 71, 72, or 73, e.g., within the [ASt Domain2]. 44. The TREM of any one of the preceding embodiments, wherein the TREM comprises a nucleotide substitution at any of positions 32, 33, 34, 35, 36, 37, or 38, e.g., within the [ACH Domain]. 45. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution at any of positions 1, 2, 3, 4, 5, 6, or 7, e.g., within the [ASt Domainl], exhibits an improvement in a functional parameter of the TREM. 46. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution at any of positions 16, 17, or 20a, e.g., within the [DH Domain], exhibits an improvement in a functional parameter of the TREM. 47. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution at any of positions 27, 28, 29, 30, 31, 39, 40, 41, 42, or 43, e.g., within the [ACH Domain], exhibits an improvement in a functional parameter of the TREM. 48. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution at any of positions 51, 59, 60, or 63, e.g., within the [TH Domain], exhibits an improvement in a functional parameter of the TREM. 356 WO 2024/216206 PCT/US2024/024492 49. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution at any of positions 66, 67, 68, 69, 70, 71, 72, or 73, e.g., within the [ASt Domain2], exhibits an improvement in a functional parameter of the TREM. 50. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution at any of positions 32, 33, 34, 35, 36, 37, or 38, e.g., within the [ACH Domain], exhibits a reduction in a functional parameter of the TREM. 51. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution comprises a scaffold, e.g., an Arg-TGA, GIn-TAG, Glu-TAG, Leu-TAG, Tyr-TAG, Ser-TAG, or Lys-TAG scaffold, e.g., a TREM corresponding to a reference sequence of SEQ IDNO: 1638, 1835, 1660, 1654, 1867, 2000, 2001, 2016, 2017, 2022, 2023, 2020, 2021, 2018, or 2019. 52. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution corresponds to a scaffold, e.g., an Arg-TGA, GIn-TAG, Glu-TAG, Leu- TAG, Tyr-TAG, Ser-TAG, or Lys-TAG scaffold, e.g., a scaffold corresponding to a reference sequenceof SEQ IDNO: 1638, 1835, 1660, 1654, 1867, 2000, 2001, 2016, 2017, 2022, 2023, 2020, 2021,2018, or 2019. 53. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution corresponds to an Arg-TGA scaffold, e.g., corresponds to a reference sequence of SEQ ID NO: 1638. 54. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution corresponds to a GIn-TAG scaffold, e.g., corresponds to a reference sequenceof SEQ IDNO: 1835, 1660, or 1654. 55. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution corresponds to a Glu-TAG scaffold, e.g., corresponds to a reference sequence of SEQ ID NO: 1867, 2000, or 2001. 357 WO 2024/216206 PCT/US2024/024492 56. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution corresponds to a Leu-TAG scaffold, e.g., corresponds to a reference sequence of SEQ ID NO: 2016 or 2017. 57. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution corresponds to a Tyr-TAG scaffold, e.g., corresponds to a reference sequence of SEQ ID NO: 2022 or 2023. 58. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution corresponds to a Ser-TAG scaffold, e.g., corresponds to a reference sequence of SEQ ID NO: 2020 or 2021. 59. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution corresponds to a Lys-TAG scaffold, e.g., corresponds to a reference sequence of SEQ ID NO: 2018 or 2019. 60. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution corresponding to a reference sequence of SEQ ID NO: 1638, 1835, 1660, 1654, 1867, 2000, 2001, 2016, 2017, 2022, 2023, 2020, 2021, 2018, or 2019, exhibitsan improvement of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 61. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution corresponding to an Arg-TGA reference sequence, e.g., SEQ ID NO: 1638, exhibits an improvement of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 62. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution at any of nucleotide positions 1, 2, 3, 4, 5, 6, or 7, e.g., in the [ASt Domainl], corresponding to an Arg-TGA reference sequence, e.g., SEQ ID NO: 1638, exhibits 358 WO 2024/216206 PCT/US2024/024492 an improvement of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 63. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution at any of nucleotide positions 32, 33, 34, 35, 36, 37, or 38, e.g., in the [ACH Domain], corresponding to an Arg-TGA reference sequence, e.g., SEQ ID NO: 1638, exhibits a reduction of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 64. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution at any of nucleotide positions 65, 66, 67, 68, 69, 70, 71, 72, or 73, e.g., in the [ASt Domain2], corresponding to an Arg-TGA reference sequence, e.g., SEQ ID NO: 1638, exhibits an improvement of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 65. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution corresponding to a Gln-TAG reference sequence, e.g., SEQ ID NO: 1835, 1660, or 1654, exhibits an improvement of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 66. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution at any of nucleotide positions 26, 27, 28, 29, 30, or 31, e.g., in the [ACH Domain], corresponding to a Gln-TAG reference sequence, e.g., SEQ ID NO: 1835, 1660, or 1654, exhibits an improvement of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 67. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution at any of nucleotide positions 32, 33, 34, 35, 36, 37, or 38, e.g., in the [ACH Domain], corresponding to a Gln-TAG reference sequence, e.g., SEQ ID NO: 1835, 1660, or 1654, exhibits a reduction of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 359 WO 2024/216206 PCT/US2024/024492 68. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution at any of nucleotide positions 39, 40, 41, 42, 43, or 44, e.g., in the [ACH Domain], corresponding to a Gln-TAG reference sequence, e.g., SEQ ID NO: 1835, 1660, or 1654, exhibits an improvement of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 69. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution corresponding to a Glu-TAG reference sequence, e.g., SEQ ID NO: 1867, 2000, or 2001, exhibits an improvement of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 70. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution at any of nucleotide positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15, e.g., in the [ASt Domainl] or the [DH Domain], corresponding to a Glu-TAG reference sequence, e.g., SEQ ID NO: 1867, 2000, or 2001, exhibits an improvement of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 71. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution at any of nucleotide positions 20a, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31, e.g., in the [DH Domain] or the [ACH Domain], corresponding to a Glu-TAG reference sequence, e.g., SEQ ID NO: 1867, 2000, or 2001, exhibits an improvement of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 72. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution at any of nucleotide positions 32, 33, 34, 35, 36, 37, or 38, e.g., in the [ACH Domain], corresponding to a Glu-TAG reference sequence, e.g., SEQ ID NO: 1867, 2000, or 2001, exhibits a reduction of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 360 WO 2024/216206 PCT/US2024/024492 73. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution at any of nucleotide positions 40, 41, 42, 43, 44, or 45, e.g., in the [ACH Domain], corresponding to a Glu-TAG reference sequence, e.g., SEQ ID NO: 1867, 2000, or 2001, exhibits an improvement of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 74. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution at any of nucleotide positions 46 or 48, e.g., in the [VL Domain], corresponding to a Glu-TAG reference sequence, e.g., SEQ ID NO: 1867, 2000, or 2001, exhibits an improvement of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 75. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution at any of nucleotide positions 59 or 60, e.g., in the [TH Domain], corresponding to a Glu-TAG reference sequence, e.g., SEQ ID NO: 1867, 2000, or 2001, exhibits an improvement of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 76. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution at any of nucleotide positions 66, 67, 68, 69, 70, 71, 72, or 73, e.g., in the [ASt Domain2], corresponding to a Glu-TAG reference sequence, e.g., SEQ ID NO: 1867, 2000, or 2001, exhibits an improvement of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 77. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution corresponding to a Leu-TAG reference sequence, e.g., SEQ ID NO: 20or 2017, exhibits an improvement of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 78. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution at any of nucleotide positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 361 WO 2024/216206 PCT/US2024/024492 , 16, 17, 18, 19, 20,21,22, 23,24, 25,26, 27, 28, 29, or 30, e.g., in the [ASt Domain 1], the [DH Domain], or the [ACH Domain], corresponding to a Leu-TAG reference sequence, e.g., SEQ ID NO: 2016 or 2017, exhibits an improvement of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 79. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution at any of nucleotide positions 32, 33, 34, 35, 36, 37, or 38, e.g., in the [ACH Domain], corresponding to a Leu-TAG reference sequence, e.g., SEQ ID NO: 2016 or 2017, exhibits a reduction of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 80. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution at any of nucleotide positions 39, 40, 41, 42, 43, 44, 45, VI1, V12, V13, V14, V15, V16, V17, VI, V2, V3, V4, V5, V27, V26, V25, V24, V23, V22, V21, 46, 47, 48, 49, or 50, e.g., in the [ACH Domain], the [VL Domain], or the [TH Domain], corresponding to a Leu-TAG reference sequence, e.g., SEQ ID NO: 2016 or 2017, exhibits an improvement of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 81. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution at any of nucleotide positions 64, 65, 66, 67, 68, 69, 70, 71, 72, or 73, e.g., in the [TH Domain] or the [ASt Domain2], corresponding to a Leu-TAG reference sequence, e.g., SEQ ID NO: 2016 or 2017, exhibits an improvement of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 82. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution corresponding to a Tyr-TAG reference sequence, e.g., SEQ ID NO: 20or 2023, exhibits an improvement of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 362 WO 2024/216206 PCT/US2024/024492 83. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution at any of nucleotide positions 4, 5, 6, or 7, e.g., in the [ASt Domainl], corresponding to a Tyr-TAG reference sequence, e.g., SEQ ID NO: 2022 or 2023, exhibits an improvement of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 84. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution at any of nucleotide positions 16, 17, or 20, e.g., in the [DH Domain], corresponding to a Tyr-TAG reference sequence, e.g., SEQ ID NO: 2022 or 2023, exhibits an improvement of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 85. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution at any of nucleotide positions 28, 29, or 30, e.g., in the [ACH Domain], corresponding to a Tyr-TAG reference sequence, e.g., SEQ ID NO: 2022 or 2023, exhibits an improvement of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 86. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution at any of nucleotide positions 32, 33, 34, 35, 36, 37, or 38, e.g., in the [ACH Domain], corresponding to a Tyr-TAG reference sequence, e.g., SEQ ID NO: 2022 or 2023, exhibits a reduction of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 87. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution at any of nucleotide positions 40, 41, 42, 43, or 44, e.g., in the [ACH Domain], corresponding to a Tyr-TAG reference sequence, e.g., SEQ ID NO: 2022 or 2023, exhibits an improvement of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 363 WO 2024/216206 PCT/US2024/024492 88. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution at any of nucleotide positions 47, 48, 49, 50, or 51, e.g., in the [VL Domain] or the [TH Domain], corresponding to a Tyr-TAG reference sequence, e.g., SEQ ID NO: 2022 or 2023, exhibits an improvement of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 89. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution at any of nucleotide positions 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70, e.g., in the [TH Domain] or the [ASt Domain2], corresponding to a Tyr-TAG reference sequence, e.g., SEQ ID NO: 2022 or 2023, exhibits an improvement of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 90. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution corresponding to a Ser-TAG reference sequence, e.g., SEQ ID NO: 20or 2021, exhibits an improvement of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 91. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution at any of nucleotide positions 3, 4, 5, or 6, e.g., in the [ASt Domainl], corresponding to a Ser-TAG reference sequence, e.g., SEQ ID NO: 2020 or 2021, exhibits an improvement of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 92. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution at any of nucleotide positions 29, 30 31, 32, or 33, e.g., in the [ACH Domain], corresponding to a Ser-TAG reference sequence, e.g., SEQ ID NO: 2020 or 2021, exhibits an improvement of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 93. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution at any of nucleotide positions 34, 35, or 36, e.g., in the [ACH Domain], 364 WO 2024/216206 PCT/US2024/024492 corresponding to a Ser-TAG reference sequence, e.g., SEQ ID NO: 2020 or 2021, exhibits an improvement of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 94. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution at any of nucleotide positions 37, 38, 39, 40, or 41, e.g., in the [ACH Domain], corresponding to a Ser-TAG reference sequence, e.g., SEQ ID NO: 2020 or 2021, exhibits an improvement of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 95. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution at any of nucleotide positions 51 or 63, e.g., in the [ACH Domain], corresponding to a Ser-TAG reference sequence, e.g., SEQ ID NO: 2020 or 2021, exhibits an improvement of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 96. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution at position 67, e.g., in the [ASt Domain2], corresponding to a Ser-TAG reference sequence, e.g., SEQ ID NO: 2020 or 2021, exhibits an improvement of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 97. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution corresponding to a Lys-TAG reference sequence, e.g., SEQ ID NO: 20or 2019, exhibits an improvement of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 98. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution at any of nucleotide positions 1, 2, 3, 4, 5, 6, or 7, e.g., in the [ASt Domainl], corresponding to a Lys-TAG reference sequence, e.g., SEQ ID NO: 2018 or 2019, exhibits an improvement of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 365 WO 2024/216206 PCT/US2024/024492 99. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution at any of nucleotide positions 17 or 18, e.g., in the [DH Domain], corresponding to a Lys-TAG reference sequence, e.g., SEQ ID NO: 2018 or 2019, exhibits an improvement of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 100. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution at any of nucleotide positions 32, 33, 34, 35, 36, 37, or 38, e.g., in the [ACH Domain], corresponding to a Lys-TAG reference sequence, e.g., SEQ ID NO: 2018 or 2019, exhibits a reduction of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 101. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution at position 37, e.g., in the [ACH Domain], corresponding to a Lys-TAG reference sequence, e.g., SEQ ID NO: 2018 or 2019, exhibits an improvement of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 102. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution at position 50, e.g., in the [TH Domain], corresponding to a Lys-TAG reference sequence, e.g., SEQ ID NO: 2018 or 2019, exhibits an improvement of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 103. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution at any of nucleotide positions 64, 65, 66, 67, 68, 69, 70, 71, 72, or 73, e.g., in the [DH Domain] or the [ASt Domain2], corresponding to a Lys-TAG reference sequence, e.g., SEQ ID NO: 2018 or 2019, exhibits an improvement of a functional parameter of the TREM, e.g., relative to the functional parameter of the reference sequence. 366 WO 2024/216206 PCT/US2024/024492 104. The TREM of any one of the preceding embodiments, wherein the TREM comprising a nucleotide substitution corresponds to a reference sequence of SEQ ID NO: 1638, 1835, 1660, 1654, 1867, 2000, 2001, 2016, 2017, 2022, 2023, 2020, 2021, 2018, or 2019. 105. The TREM of any one of the preceding embodiments, wherein the TREM comprises a non-naturally occurring modification. 106. The TREM of embodiment 105, wherein the non-naturally occurring modification is present on the 2’-position of a nucleotide sugar or within the internucleotide region (e.g., a backbone modification). 107. The TREM of any one of embodiments 105-106, wherein the non-naturally occurring modification is selected from a 2’-O-methyl (2-OMe), 2’-halo (e.g., 2’F or 2’Cl), 2’-O- methoxyethyl (2’MOE), or 2’deoxy modification. 108. The TREM of any one of embodiments 105-107, wherein the non-naturally occurring modification is a phosphorothioate modification. 109. The TREM of any one of embodiments 105-108, wherein the TREM comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 additional non-naturally occurring modifications compared with a TREM provided in FIG. 3 (e.g., 2’-ribose modifications or an internucleotide modification, e.g., 2’OMe, 2’-halo, 2’-M0E, 2’-deoxy, or phosphorothiorate modifications). 110. The TREM of any one of the preceding embodiments, wherein the TREM comprises a pattern of non-naturally occurring modifications selected from the patterns listed in Table 6. 111. The TREM of any one of the preceding embodiments, wherein:(i) the non-naturally occurring modification is present at a nucleotide position which corresponds to one or more of nucleotides 1-9 of SEQ ID NO: 734; and/or(ii) the TREM differs from the nucleotide sequence of SEQ ID NO: 734 by about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides. 367 WO 2024/216206 PCT/US2024/024492 112. The TREM of any one of the preceding embodiments, wherein:(i) the non-naturally occurring modification is present at a nucleotide position which corresponds to one or more of nucleotides 10-19 of SEQ ID NO: 734; and/or(ii) the TREM differs from the nucleotide sequence of SEQ ID NO: 734 by about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides. 113. The TREM of any one of the preceding embodiments, wherein:(i) the non-naturally occurring modification is present at a nucleotide position which corresponds to one or more of nucleotides 20-29 of SEQ ID NO: 734; and/or(ii) the TREM differs from the nucleotide sequence of SEQ ID NO: 734 by about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides. 114. The TREM of any one of the preceding embodiments, wherein:(i) the non-naturally occurring modification is present at a nucleotide position which corresponds to one or more of nucleotides 30-39 of SEQ ID NO: 734; and/or(ii) the TREM differs from the nucleotide sequence of SEQ ID NO: 734 by about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides. 115. The TREM of any one of the preceding embodiments, wherein:(i) the non-naturally occurring modification is present at a nucleotide position which corresponds to one or more of nucleotides 40-49 of SEQ ID NO: 734; and/or(ii) the TREM differs from the nucleotide sequence of SEQ ID NO: 734 by about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides. 116. The TREM of any one of the preceding embodiments, wherein:(i) the non-naturally occurring modification is present at a nucleotide position which corresponds to one or more of nucleotides 50-59 of SEQ ID NO: 734; and/or(ii) the TREM differs from the nucleotide sequence of SEQ ID NO: 734 by about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides. 368 WO 2024/216206 PCT/US2024/024492 117. The TREM of any one of the preceding embodiments, wherein:(i) the non-naturally occurring modification is present at a nucleotide position which corresponds to one or more of nucleotides 60-69 of SEQ ID NO: 734; and/or(ii) the TREM differs from the nucleotide sequence of SEQ ID NO: 734 by about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides. 118. The TREM of any one of the preceding embodiments, wherein:(i) the non-naturally occurring modification is present at a nucleotide position which corresponds to one or more of nucleotides 70-76 of SEQ ID NO: 734; and/or(ii) the TREM differs from the nucleotide sequence of SEQ ID NO: 734 by about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides. 119. The TREM of any one of the preceding embodiments, wherein the TREM comprises the nucleotide sequence of SEQ ID NO: 743. 120. The TREM of any one of the preceding embodiments, wherein the TREM comprises the nucleotide sequence of SEQ ID NO: 652. 121. The TREM of any one of the preceding embodiments, wherein the TREM comprises the nucleotide sequence of SEQ ID NO: 702. 122. The TREM of any one of the preceding embodiments, wherein the TREM comprises the nucleotide sequence of SEQ ID NO: 627. 123. The TREM of any one of the preceding embodiments, wherein the TREM comprises the nucleotide sequence of SEQ ID NO: 1150. 124. The TREM of any one of the preceding embodiments, wherein the TREM comprises the nucleotide sequence of SEQ ID NO: 1151. 369 WO 2024/216206 PCT/US2024/024492 125. The TREM of any one of the preceding embodiments, wherein the TREM comprises the nucleotide sequence of SEQ ID NO: 794. 126. The TREM of any one of the preceding embodiments, wherein the TREM comprises the nucleotide sequence of SEQ ID NO: 641. 127. The TREM of any one of the preceding embodiments, wherein the TREM comprises the nucleotide sequence of SEQ ID NO: 710. 128. The TREM of any one of the preceding embodiments, wherein the non-naturally occurring modification is present at a nucleotide position which corresponds to one or more of nucleotides 1-76, according to the CtNS. 129. A TREM (e.g., a TREM provided in Table 7) that has a pattern of non-naturally occurring modifications according to a pattern in Table 6 (e.g., a pattern selected from Pattern Nos. 1-32). 130. A TREM (e.g., a TREM provided in Table 7) that has the pattern of non-naturally occurring modifications according to Pattern No. 1 in Table 6. 131. A TREM (e.g., a TREM provided in Table 7) that has the pattern of non-naturally occurring modifications according to Pattern No. 2 in Table 6. 132. A TREM (e.g., a TREM provided in Table 7) that has the pattern of non-naturally occurring modifications according to Pattern No. 3 in Table 6. 133. A TREM (e.g., a TREM provided in Table 7) that has the pattern of non-naturally occurring modifications according to Pattern No. 4 in Table 6. 134. A TREM (e.g., a TREM provided in Table 7) that has the pattern of non-naturally occurring modifications according to Pattern No. 5 in Table 6. 370 WO 2024/216206 PCT/US2024/024492 135. A TREM (eg., a TREM provided in Table 7) that has the pattern of non-naturally occurring modifications according to Pattern No. 6 in Table 6. 136. A TREM (e.g., a TREM provided in Table 7) that has the pattern of non-naturally occurring modifications according to Pattern No. 7 in Table 6. 137. A TREM (e.g., a TREM provided in Table 7) that has the pattern of non-naturally occurring modifications according to Pattern No. 8 in Table 6. 138. A TREM (e.g., a TREM provided in Table 7) that has the pattern of non-naturally occurring modifications according to Pattern No. 9 in Table 6. 139. A TREM (e.g., a TREM provided in Table 7) that has the pattern of non-naturally occurring modifications according to Pattern No. 10 in Table 6. 140. A TREM (e.g., a TREM provided in Table 7) that has the pattern of non-naturally occurring modifications according to Pattern No. 11 in Table 6. 141. A TREM (e.g., a TREM provided in Table 7) that has the pattern of non-naturally occurring modifications according to Pattern No. 12 in Table 6. 142. A TREM (e.g., a TREM provided in Table 7) that has the pattern of non-naturally occurring modifications according to Pattern No. 13 in Table 6. 143. A TREM (e.g., a TREM provided in Table 7) that has the pattern of non-naturally occurring modifications according to Pattern No. 14 in Table 6. 144. A TREM (e.g., a TREM provided in Table 7) that has the pattern of non-naturally occurring modifications according to Pattern No. 15 in Table 6. 371 WO 2024/216206 PCT/US2024/024492 145. A TREM (e.g., a TREM provided in Table 7) that has the pattern of non-naturally occurring modifications according to Pattern No. 16 in Table 6. 146. A TREM (e.g., a TREM provided in Table 7) that has the pattern of non-naturally occurring modifications according to Pattern No. 17 in Table 6. 147. A TREM (e.g., a TREM provided in Table 7) that has the pattern of non-naturally occurring modifications according to Pattern No. 18 in Table 6. 148. A TREM (e.g., a TREM provided in Table 7) that has the pattern of non-naturally occurring modifications according to Pattern No. 19 in Table 6. 149. A TREM (e.g., a TREM provided in Table 7) that has the pattern of non-naturally occurring modifications according to Pattern No. 20 in Table 6. 150. A TREM (e.g., a TREM provided in Table 7) that has the pattern of non-naturally occurring modifications according to Pattern No. 21 in Table 6. 151. A TREM (e.g., a TREM provided in Table 7) that has the pattern of non-naturally occurring modifications according to Pattern No. 22 in Table 6. 152. A TREM (e.g., a TREM provided in Table 7) that has the pattern of non-naturally occurring modifications according to Pattern No. 23 in Table 6. 153. A TREM (e.g., a TREM provided in Table 7) that has the pattern of non-naturally occurring modifications according to Pattern No. 24 in Table 6. 154. A TREM (e.g., a TREM provided in Table 7) that has the pattern of non-naturally occurring modifications according to Pattern No. 25 in Table 6. 372 WO 2024/216206 PCT/US2024/024492 155. A TREM (e.g., a TREM provided in Table 7) that has the pattern of non-naturally occurring modifications according to Pattern No. 26 in Table 6. 156. A TREM (e.g., a TREM provided in Table 7) that has the pattern of non-naturally occurring modifications according to Pattern No. 27 in Table 6. 157. A TREM (e.g., a TREM provided in Table 7) that has the pattern of non-naturally occurring modifications according to Pattern No. 28 in Table 6. 158. A TREM (e.g., a TREM provided in Table 7) that has the pattern of non-naturally occurring modifications according to Pattern No. 29 in Table 6. 159. A TREM (e.g., a TREM provided in Table 7) that has the pattern of non-naturally occurring modifications according to Pattern No. 30 in Table 6. 160. A TREM (e.g., a TREM provided in Table 7) that has the pattern of non-naturally occurring modifications according to Pattern No. 31 in Table 6. 161. A TREM (e.g., a TREM provided in Table 7) that has the pattern of non-naturally occurring modifications according to Pattern No. 32 in Table 6. 162. A pharmaceutical composition comprising a TREM of any one of the preceding embodiments. 163. The pharmaceutical composition of embodiment 162, further comprising a pharmaceutically acceptable component, e.g., an excipient. 164. A lipid nanoparticle formulation comprising a TREM of any one of embodiments 1-163. 165. A lipid nanoparticle formulation comprising a pharmaceutical composition of embodiment164. 373 WO 2024/216206 PCT/US2024/024492 166. A method of treating a subject having a disease or disorder associated with a PTC comprising administering to the subject a TREM, TREM core fragment, or TREM fragment described herein (e.g., a TREM of any one of the preceding claims), thereby treating the subject having the disease or disorder. 167. The method of embodiment 166, wherein the disease or disorder associated with a PTC comprises Hemophilia B, Fabry disease, Usher syndrome, or CLN2 disease. 168. A method of modulating a functional parameter of a tRNA effector molecule (TREM),wherein the TREM comprises a sequence of Formula (1):[Ll]x-[ASt Domain l]-[L2]x-[DH Domain]-[L3]x-[ACH Domain] [VL Domain]-[TH D0main]-[L4]x-[ASt Domain2]-[L5]x (I), wherein:independently, [Li] and [VL Domain], are optional;x is 0 or 1; andthe TREM comprises a nucleotide substitution (e.g., a nucleotide mutation) in the TREM capable of modulating a functional parameter of the TREM;thereby modulating the functional parameter of the TREM.

EXAMPLES Table of Contents for Examples Example 1 Synthesis of modified TREMsExample 2 HPLC and MS analysis of modified TREMsExample 3 Analysis of modified TREMs via anion-exchange HPLCExample 4 Analysis of TREMs via PAGE Purification and AnalysisExample 5 Deprotection of synthesized TREMExample 6 Characterization of chemically modified TREMs for readthrough of a premature termination codon (PTC) in a reporter proteinExample 7 Characterization of chemically modified TREMs for readthrough of a premature termination codon (PTC) in a disease reporter cell line 374 WO 2024/216206 PCT/US2024/024492 Example 8 Pooled screen for increased premature termination codon (PTC) readthrough activity of exemplary TREMs having nucleotide substitutions.

Example 1: Synthesis of modified TREMs Generally, TREM molecules (e.g., modified TREMs) may be chemically synthesized and purified by HPLC according to standard solid phase synthesis methods using phosphoramidite chemistry, (see, e.g., Scaringe S. et al. (2004) Cwt Protoc Nucleic Acid Chern, 2.10.1-2.10.16; Usman N. etal. (1987) J. Am. Chern. Soc, 109, 7845-7854). Individually modified TREM molecules containing one or more 2’-methoxy (2‘OMe), 2‘fluoro (2’F), 2’-meth oxy ethyl (2’ - MOE), or phosphorothioate (PS) modifications were prepared using TREM-Arg-TGA sequences as a framework according to phosphoramidite technology on solid phase used in oligonucleotide synthesis. For clarity, the arginine non-cognate TREM molecule named TREM-Arg-TGA contains the sequence of ARG-UCU-TREM body but with the anticodon sequence corresponding to UCA instead of UCU (i.e., SEQ ID NO: 622).To make the 2’0Me modified TREMs, the following 2’-O-methyl phosphoramidites were used: (5’-O-dimethoxytrityl-N6-(benzoyl)-2 ’-O-methyl-adenosine-3 ’-O-(2-cyanoethyl- N,N-diisopropy-lamino) phosphoramidite, 5’-O-dimethoxy-trityl-N4-(acetyl)-2 ’-O-methyl- cytidine-3 ’-O-(2-cyanoethyl-N,N-diisopropyl-amino) phosphoramidite, (5’- O -dimethoxytrityl- N2-(isobutyryl)-2 ’-O-methyl-guanosine-3 ’-O-(2-cyano-ethyl-N,N-diisopropylamino)- phosphoramidite, and 5’-O-dimethoxy-trityl-2 ’-O-methyluridine-3 ’- O -(2-cyanoethyl-N,N- diisopropylamino)phosphoramidite. To make the 2’-deoxy and 2’-F modified TREMs, analogous 2’-deoxy and 2’-fluoro-phosphoramidites with the same protecting groups as the 2’-O-methyl RNA amidites were used. To make the 2’-MOE modified TREMs, the following 2’-M0E- phosphoramidites were used: 5’-O-(4,4’-Dimethoxytrityl)-2 ’-O-methoxyethyl-N6-benzoyl- adenosine -3’-O-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite, 5’-O-(4,4’- Dimethoxytrityl)-2 ’-O-methoxyethyl-5-methyl-N4-benzoyl- cytidine-3 ’-O-[(2-cyanoethyl)- (N,N-diisopropyl)]-phosphoramidite, 5’-O-(4,4’-Dimethoxytrityl)-2 ’-O-methoxyethyl-N2- isobutyryl- guanosine-3 ’-O-[(2-cyanoethyl)-(N,N-diisopropyl)]-phosphoramidite, 5’-O-(4,4’- Dimethoxytrityl)-2 ’-O-methoxyethyl-5-methyl-uridine-3 ’-O-[(2-cyanoethyl)-(N,N-diisopropyl)]- phosphoramidite. 375 WO 2024/216206 PCT/US2024/024492 During the oligonucleotide synthesis via this phosphoramidites approach, the phosphorothioate was introduced by oxidizing the phosphite triester using a sulfur transfer reagent, such as tetraethylthiuram disulfide (TETD), bis(O,O-diisopropoxy phosphinothioyl) disulfide (Stec ’s reagent), 3H-l,2-benzodithiol-3-one-l,l,-dioxi de (Beaucage reagent), phenylacetyl disulfide (PADS), 3-ethoxy-l,2,4-dithiazoline-5-one (EDITH), l,2-dithiazole-5- thione (xanthane hydride or ADTT), 3-((dimethylamino-methylidene)amino)-3H-l,2,4- dithiazole-3-thione (DDTT), dimethylthiuram disulfide (DTD), 3-phenyl-l,2,4-dithiazoline-5- one (PolyOrg Sulfa or POS).FIG. 3 describes a series of singly and multiply modified TREMs synthesized according to this procedure. The sequences of each of these TREMs are provided in the table, wherein r: ribonucleotide; m; 2’-OMe; *: PS linkage; f: 2’-fluoro; moe; 2’-moe; d: deoxyribonucleotide; 5MeC: 5-methylcytosine. Thus, for example, mA represents 2’-O-methyl adenosine, moe5MeC represents 2’-M0E nucleotide with 5-methylcytosine nucleobase, and dA represents an adenosine deoxyribonucleotide. Example 2: HPLC and MS analysis of modified TREMs Chemically modified TREM molecules may be analyzed by HPLC, for example, to evaluate the purity and homogeneity of the compositions. A Waters Aquity UPLC system using a Waters BEH C18 column (2.1 mm x 50 mm x 1.7 pm) may be used for this analysis. Samples may be prepared by dissolving 0.5 nmol of the TREM in 75 pL of water and injecting 2 pL of the solution. The buffers used may be 50 mM dimethylhexylammonium acetate with 10% CH3CN (acetonitrile) as buffer A and 50 mM dimethylhexylammonium acetate with 75% CHCN as buffer B (gradient 25-75% buffer B over 5 mins), with a flow rate of 0.5 mL/min at °C. ESI-LCMS data for the chemically modified TREMs may be acquired on a Thermo Ultimate 3000-LTQ-XL mass spectrometer.FIG. 3 describes a series of singly and multiply modified TREMs synthesized according to the protocol outlined in Example 1. The calculated and detected molecular weights for each sequence were determined as outlined herein. Example 3: Analysis of modified TREMs via anion-exchange HPLC This example describes the quality control of a synthesized TREM via anion-exchange HPLC. Using the Dionex DNA-Pac-PA-100 column, a gradient is employed using HPLC buffer A and HPLC buffer B. 0.5 ODUs of a sample that has been dissolved in H20 or Tris buffer, pH 376 WO 2024/216206 PCT/US2024/024492 7.5 is injected onto the gradient. The gradient employed is based on oligonucleotide length and can be applied according to Table 13. The parameters provided in Table 14 can be used to program a linear gradient on the HPLC analyzer. Table 13:Oligonucleotide length and gradient percentages Length (bases) Gradient (%B) 0-5 0-306-10 10-4011-16 20-5017-32 30-6033-50 40-70>50 50-80 Table 14:Parameters for a linear gradient on HPLC analyzer Time (min) Flow (mL/min) % Buffer A % Buffer B 1.5 100 01.5 100 01.5 70a 30a1.5 40a 60a15.5 2.5 0 1002.5 0 10017.25 2.5 100 02.5 100 0823.1 1.5 100 01.5 100 00.1 100 0 Example 4: Analysis of TREMs via PAGE Purification and Analysis This example describes the quality control of a synthesized TREM via PAGE Purificationand Analysis. Gel purification and analysis of 2’-ACE protected RNA follows standard protocols 377 WO 2024/216206 PCT/US2024/024492 for denaturing PAGE (Ellington and Pollard (1998) In Current Protocols in Molecular Biology, Chanda, V). Briefly, the 2’-ACE protected oligo is resuspended in 200 mL of gel loading buffer. Invitrogen™ NuPAGE™ 4-12% Bis-Tris Gels or similar gel is prepared in gel apparatus.Samples are loaded and gel ran at 50-120 W, maintaining the apparatus at 40°C. When complete, the gel is exposed to ultraviolet (UV) light at 254 nm to visualize the purity of the RNA using UV shadowing. If necessary, the desired gel band is excised with a clean razor blade. The gel slice is crushed and 0.3M NaOAc elution buffer is added to the gel particles, and soaked overnight. The mixture is decanted and filtered through a Sephadex column such as Nap-10 or Nap-25. Example 5: Deprotection of synthesized TREM This example describes the deprotection of a TREM made according to an in vitro synthesis method. The 2’-protecting groups are removed using 100 mM acetic acid, pH 3.8. The formic acid and ethylene glycol byproducts are removed by incubating at 60°C for 30 min followed by lyophilization or SpeedVac-ing to dryness. After this final deprotection step, the oligonucleotides are ready for use. Example 6. Characterization of chemically modified TREMs for readthrough of a premature termination codon (PTC) in a reporter protein This example describes an assay to test the ability of a chemically modified TREM to readthrough a PTC in a cell line expressing a reporter protein having a PTC. This protocol describes analysis of chemically modified TREM (i.e., Arg-TGA), though a non-cognate TREM specifying any one of the other amino acids can also be used.A cell line engineered to stably express the NanoLuc reporter construct containing a premature termination codon (PTC) may be generated using the Flpin and/or JumpIN cell system (ThermoFisher Scientific, USA) according to the manufacturer ’s instructions. The NanoLuc reporter can also be modified with a destabilizing PEST domain at its C-terminus to reduce the protein half-life. Delivery of the chemically modified TREMs into the NanoLuc reporter cells is carried out via a reverse transfection reaction using lipofectamine RNAiMAX (ThermoFisher Scientific, USA) according to manufacturer instructions. Briefly, 0.15uL of a 5uM solution of chemically modified TREM sample are diluted in a 7.35uL RNAiMAX/OptiMEM mixture. After 30min gentle mixing at room temperature, the 7.5uL TREM/transfection mixture is added to a 384-well plate and kept still for 20-30min before adding the cells stably expressing the 378 WO 2024/216206 PCT/US2024/024492 NanoLuc reporter construct containing a PTC. The NanoLuc reporter cells are harvested and diluted to 4x 105 cells/mL in complete growth medium, and 30uL of the diluted cell suspension is added and mixed to the plate containing the TREMTo monitor the efficacy of the chemically modified TREM to read through the PTC in the reporter construct at 24 or 48 hours after TREM delivery into cells, a NanoGio bioluminescent assay (Promega, USA) may be performed according to manufacturer instruction. Briefly, for cells that are to be assayed after 48 hours, 30uL complete growth medium is added to the 384-well plate 24 hours post-transfection to dilute the transfection reagent for cell health. At the time of harvest, either 24- or 48-hours post-transfection, cell media is removed and plates are stored at -80C. To perform the assay, thaw plates are thawed on ice for 1 hour, then transfered to room temperature and allowed to equilibrate. Add 15 uL room-temperature complete growth media to each well. NanoGio reagent is prepared by mixing the buffer with substrate in a 50:ratio. 15uL of mixed NanoGio reagent is added to each well of the 384-well plate and mixed on the shaker at 600rpm for lOmin. Then the plate is centrifuged at 100g for Imin, followed by a 5min incubation step at room temperature before measuring sample bioluminescence. As a positive control, a host cell expressing the NanoLuc reporter construct with a PTC is used and transfected with a previously-identified unmodified, active TREM. As a negative control, a host cell expressing the NanoLuc reporter construct with a PTC is used, but no TREM is transfected. The efficacy of the chemically modified TREMs is measured as a ratio of the NanoLuc luminescence in the experimental sample to the NanoLuc luminescence of the positive control or as a ratio of the NanoLuc luminescence in the experimental sample to the NanoLuc luminescence of the negative control. It is expected that if the sample TREM is functional, it may be able to read-through the stop mutation in the NanoLuc reporter and produce a luminescent reading higher than the luminescent reading measured in the negative control. If the sample TREM is not functional, the stop mutation is not rescued, and luminescence less or equal to the negative control is detected.The impacts of chemical modifications were evaluated in singly and multiply modified TREM sequences and are summarized in FIG. 3. In this figure, the TREMs are annotated as follows: r: ribonucleotide; m: 2’-0Me; *: PS linkage; f 2’-fluoro; moe: 2’-moe; d: deoxyribonucl eotide; 5MeC: 5-methylcytosine. Thus, for example, mA represents 2’-O-methyl 379 WO 2024/216206 PCT/US2024/024492 adenosine, moe5MeC represents 2’-MOE nucleotide with 5-methylcytosine nucleobase, and dA represents an adenosine deoxyribonucleotide.FIG. 3 also summarizes the results of the activity screen in column "Activity A" for measurements made using NanoLuc reporter cells at 48 hours post-transfection, which reported as 10g2 fold changes compared with the appropriate unmodified TREM, wherein "1" indicates less than a 1 10g2 fold change; "2" indicates greater than or equal to 1 and less than 3.32 10gfold change; and "3" indicates greater than or equal to 3.32 10g2 fold change. The results show that certain modifications were tolerated at many positions, but particular sites were sensitive to modification or exhibited improved activity when modified. Example 7: Characterization of chemically modified TREMs for readthrough of a premature termination codon (PTC) in a disease reporter cell line This example describes an assay to test the ability of an exemplary TREM to readthrough a PTC in a cell line expressing a disease reporter protein bearing the PTC.Host cell modificationA cell line engineered to stably express a HaloTag and HiBiT-tagged disease reporter construct containing a premature termination codon (PTC), such as Factor IX at position 2ITIXr248x Factor IX at position 29 UdXu29x Factor IX at position 333 (FI^3iX), or Rhodopsin at position 334 (Rho s334x ) was generated using the Jump-In system according to manufacturer ’s instructions. Briefly, Jump-In GripTite HEK293 (Thermo Scientific A14150) cells were co- transfected with an expression vector containing the disease reporter, such as pJTI-R4-DEST- CMV-FIX-R298X-HaloTag-HiBiT-pA for FIX8-29821 to make the Factor IX disease reporter expressing cell line, and a pJTI-R4-Int PhiC3 1 integrase expression vector using Lipofectamine2000 according to manufacturer ’s instructions. After 24 hours, the media was replaced with fresh media. The next day, the cells were re-seeded at 50% confluency and selected with lOug/mL Blasticidin and 600ug/mL G418 for 7 days with media change every days. The remaining cells were expanded and tested for reporter construct expression. Translation suppression assayExemplary TREMs were synthesized and characterized as described herein, then transfected into cells. Forty-eight hours after TREM delivery into cells, conditioned media was collected, fresh media was added to the cells and allowed to equilibrate to room temperature. To measure the efficacy of arginine TREMs in PTC readthrough, full-length HiBiT-tagged disease 380 WO 2024/216206 PCT/US2024/024492 reporter protein was assayed in both cells, and 48-hour conditioned media. Briefly, reconstituted Nano-Glo® HiBiT Lytic Reagent was added to both cells containing fresh media and 48-hour conditioned media at a 1:1 v/v ratio, mixed on an orbital shaker at 500rpm for 10 minutes, and incubated at room temperature for 10 minutes. The HiBiT-tagged disease reporter activity is measured by reading the luminescence in a plate reader. Example 8: Pooled screen for increased premature termination codon (PTC) readthrough activity of exemplary TREMs having nucleotide substitutions. This example describes a pooled screen of a plurality of exemplary TREMs bearing nucleotide substitutions to identify nucleotide substitutions that increase the premature termination codon (PTC) readthrough activity of the TREM.Pool designTo perform a pooled screen of TREMs having nucleotide substitutions, a library of 5,0to 100,000 unique TREM sequences were designed using saturating or sub-saturating mutagenesis strategies. The TREMs typically contain 1-10 nucleotide substitutions relative to one or more starting sequences. In this example, the library comprised TREMs corresponding to a parental Gln-TAG TREM sequence (e.g., SEQ ID NOs: 1654, 1660, or 1835) Pool constructionThe TREMs are synthesized as a single-stranded DNA oligo pool and then cloned using established techniques (e.g., as described in Yau et al., Methods Mol Biol, 2018) into a lentiviral vector that expresses the candidate tRNA from a P01III promoter. The lentiviral pool is transduced into a reporter cell line where readthrough of a premature termination codon (PTC) in a reporter gene produces a fluorescent signal.Screen for premature termination codon (PTC) read-throughCells positive for fluorescence are isolated using fluorescence-activated cell sorting and the abundance of each TREM candidate in the positive population is compared to that of the input population using Next-Generation sequencing.An enrichment score is calculated for each TREM as the relative abundance of each TREM in the positive population relative to the input population, with a higher enrichment score indicating that a TREM was positively associated with PTC readthrough. Each screen additionally contains 50 negative control sequences that are not expected to produce PTC readthrough and the enrichment scores are used to determine a hit threshold that excludes all or 381 WO 2024/216206 PCT/US2024/024492 nearly all negative control sequences. Additionally, many human tRNAs that are converted to recognize the PTC are included and some of these are expected to score above the hit threshold. Novel TREMs above the hit threshold in two biological replicates are classified as hits. For example, a pooled screen for TREMs that recognize a TAG PTC and insert Gin was performed on 83,945 candidate tRNAs, with 801 candidates showing an enrichment score above the hit threshold of 2.5 in both replicates, e.g., as shown in FIG. 17.Hit validationA subset of hits were selected to be validated as individually synthesized RNA oligonucleotides. Hits for validation are selected based on two criteria: (i) They must span a range of enrichment scores above the hit threshold; (ii) They must differ from the parent sequence in different regions of the TREM two-dimensional structure. The diversity in enrichment scores and TREM sequences indicate which regions are amenable to mutations to produce an active PTC-suppressing TREM. The selected hits are synthesized as oligos and validated using a luciferase reporter assay. For example, 138 of the 801 hits from the Gln-TAG pooled screen shown in FIG. 17 were selected for validation as synthesized RNA oligonucleotides and evaluated in a luciferase reporter assay at two concentrations. As shown in FIG. 18, essentially all Gln-TAG candidates validated as having activity above background, and the majority were more active than the initial sequence from which candidates were derived.Based on the screen and validation data, the hits identified during the Gln-TAG pooled screen represent a set of sequence changes to a starting TREM that typically lead to a new TREM sequence with maintained or greater PTC-suppression activity. The sequence changes that are overrepresented among hits in terms of nucleotide and structural changes across each position and TREM region are used to identify sequences changes that are likely to increase the activity of a starting Gln-TAG TREM when used individually or in combination. Each hit may provide a new sequence variant that can be used as the starting sequence for further rounds of pooled screening to improve its activity and identify additional nucleotide substitutions that may not have been among the dominant changes observed in a prior round of screening.In addition to validating many Gln-TAG hits as synthesized oligonucleotides, 47 of these TREMs were additionally evaluated for their ability to promote PTC readthrough when delivered as lentiviral particles. The candidate TREMs selected here span a range of enrichment scores 382 WO 2024/216206 PCT/US2024/024492 above the hit threshold, differ from the parent sequence in different regions of the TREM two- dimensional structure, and must have also been evaluated as synthesized oligonucleotides.For each selected TREM, a lentiviral transfer plasmid that will express the TREM from a P01III promoter was produced using standard molecular cloning methods and then packaged to produce lentiviral particles. Cells that are transduced with the virus will express the TREM as well as a puromycin resistance gene. The titer of each virus was measured and then luciferase reporter cells with a TAG PTC mutation were transduced at a multiplicity of infection of 0.3 to create a cell line for each TREM candidate. Cells that were successfully transduced were selected using puromycin (2 ug/mL) over the next several days. At 7 days post-transduction 20,000 cells from each cell line were replated in a 96-well plate, and after growing a further 2 days cells were lysed and analyzed by luciferase assay to determine the PTC readthrough activity mediated by each TREM candidate. As shown in FIG. 22, the activity of the selected candidates delivered as synthesized oligonucleotides or lentiviral particles were well correlated, demonstrating that sequence engineering results from the pooled screens are suitable for RNA or viral delivery.The results of pooled screens for each of various TREM scaffolds are summarized in FIGs. 23-25. FIG. 23 shows the oligo sequences of validated hits from the pooled screens and the 10g2 PTC read-through activity of each TREM at low, intermediate, and high doses relative to the parent TREM, wherein "1" indicates no activity; "2" indicates active; and "3" indicates high activity. In this figure, the TREMs are annotated as follows: r: ribonucleotide; m: 2’-0Me. The results show that nucleotide substitutions at particular positions resulted in high PTC readthrough activity. FIG. 24 shows the nucleotide substitutions of validated hits listed in FIG. 23, the type of substitution, and the PTC read-through activity relative to the parent TREM at low and high doses, wherein "I" indicates less activity than the parent TREM; "2" equal activity as the parent TREM; and "3" indicates higher activity than the parent TREM. The results show that nucleotide substitutions at particular positions resulted in high PTC readthrough activity. FIG. 25 shows the PTC read-through activity of hits delivered as synthesized oligonucleotides as listed in FIGs. and 24 in comparison with PTC read-through activity of the same hits delivered as lentiviral particles, wherein column Activity A lists the activity from lentiviral delivery and "I" indicates no activity; "2" indicates active; and "3" indicates high activity; column Activity B lists the activity from lentiviral delivery relative to the parent TREM and "I" indicates less activity than the parent TREM; "2" equal activity as the parent TREM; and "3" indicates higher activity than 383 WO 2024/216206 PCT/US2024/024492 the parent TREM; column Activity C lists the activity from synthesized oligonucleotide delivery as shown in FIG. 23 and "1" indicates no activity; "2" indicates active; and "3" indicates high activity; and column Activity D lists the activity from synthesized oligonucleotide delivery relative to the parent TREM as shown in FIG. 24 and "1" indicates less activity than the parentTREM; "2" equal activity as the parent TREM; and "3" indicates higher activity than the parent TREM. The results show that the PTC read-through activity of hits is about equivalent when validated as synthesized oligonucleotides and by lentiviral delivery, e.g., the activity is not affected by the validation method of hits from the pooled screen. 384

Claims

WO 2024/216206 PCT/US2024/024492 What is claimed is:

1. A tRNA effector molecule (TREM) comprising a sequence of Formula (1):[Ll]x-[ASt Domainl]-[L2]x-[DH Domain]-[L3]x-[ACH Domain] -[VL Domain]-[TH D0main]-[L4]x-[ASt Domain2]-[L5]x (1), wherein:independently, [Li] and [VL Domain], are optional;x is 0 or 1; andthe TREM comprises a nucleotide substitution (e.g., a nucleotide mutation) in the TREM capable of modulating a functional parameter of the TREM.

2. The TREM of claim I, wherein the functional parameter comprises activity of the TREM or stability of the TREM.

3. The TREM of any one of the preceding claims, wherein the functional parameter comprises premature termination codon (PTC) readthrough activity of the TREM (e.g., an increased level of PTC readthrough activity or decreased PTC readthrough activity), e.g., in a sample (e.g., a cell) or in a subject.

4. The TREM of any one of the preceding claims, wherein the functional parameter comprises stability of the TREM (e.g., increased stability of the TREM or decreased stability of the TREM), e.g., in a sample (e.g., a cell) or in a subject.

5. The TREM of any one of the preceding claims, wherein the functional parameter is selected from:(a) protein translation;(b) expression level (e.g., of polypeptide or protein, or mRNA);(c) post-translational modification of polypeptide or protein;(d) folding (e.g., of polypeptide or protein, or mRNA),(e) structure (e.g., of polypeptide or protein, or mRNA),(f) transduction (e.g., of polypeptide or protein), 385 WO 2024/216206 PCT/US2024/024492 (g) compartmentalization (e.g., of polypeptide or protein, or mRNA),(h) incorporation (e.g., of polypeptide or protein, or mRNA) into a supermolecular structure, e.g., incorporation into a membrane, proteasome, or ribosome,(i) incorporation into a multimeric polypeptide, e.g., a homo or heterodimer, and/or(j) stability.

6. The TREM of claim 5, wherein the functional parameter further comprises:(1) modulation of a signaling pathway, e.g., a cellular signaling pathway which is downstream or upstream of the protein encoded by the endogenous ORF having a first sequence or PTC;(2) cell fate modulation;(3) ribosome occupancy modulation;(4) protein translation modulation;(5) mRNA stability modulation;(6) protein folding and structure modulation;(7) protein transduction or compartmentalization modulation; and/or(8) protein stability modulation.

7. The TREM of any one of the preceding claims, wherein the TREM comprises a TREM having at least 70%, 75%, 80%, 85%, 90%, 95%, or 99% sequence identity with a TREM provided in FIGs. 3 or 23.

8. The TREM of any one of the preceding claims, wherein the TREM comprises a nucleotide sequence that differs by 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or nucleotides from the nucleotide sequence of a TREM provided in FIGs. 3 or 23.

9. The TREM of any one of the preceding claims, wherein the TREM comprises a nucleotide sequence that differs by 10, 15, 20, 25, 30, 35 or 40 nucleotides from the nucleotide sequence of a TREM provided in FIGs. 3 or 23. 386 WO 2024/216206 PCT/US2024/024492

10. The TREM of any one of the preceding claims, wherein the TREM comprises a nucleotide sequence that differs by more than 5 nucleotides from the nucleotide sequence of a TREM provided in FIGs. 3 or 23.

11. The TREM of any one of the preceding claims, wherein the TREM comprises a nucleotide sequence that differs by more than 10 nucleotides from the nucleotide sequence of a TREM provided in FIGs. 3 or 23.

12. The TREM of any one of the preceding claims, wherein the TREM comprises a sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides from the nucleotide sequence of a TREM provided in FIGs. 3 or 23.

13. The TREM of any one of the preceding claims, wherein the TREM comprises a nucleotide sequence that differs by no more than 10, 15, 20, 25, 30, 35 or 40 nucleotides from the nucleotide sequence of a TREM provided in FIGs. 3 or 23.

14. The TREM of any one of the preceding claims, wherein the TREM comprises a nucleotide sequence that differs by no more than 1 nucleotide from the nucleotide sequence of a TREM provided in FIGs. 3 or 23.

15. The TREM of any one of the preceding claims, wherein the TREM comprises a nucleotide sequence that differs by no more than 5 nucleotides from the nucleotide sequence of a TREM provided in FIGs. 3 or 23.

16. The TREM of any one of the preceding claims, wherein the TREM comprises a nucleotide sequence that differs by no more than 10 nucleotides from the nucleotide sequence of a TREM provided in FIGs. 3 or 23.

17. The TREM of any one of the preceding claims, wherein the TREM comprises a nucleotide substitution within the [ASt Domainl], e.g., the nucleotide substitution is at any of positions 1, 2, 3, 4, 5, 6, 7, 8, or 9 within the [ASt Domainl], 387 WO 2024/216206 PCT/US2024/024492

18. The TREM of any one of the preceding claims, wherein the TREM comprises a nucleotide substitution within the [DH Domain], e.g., the nucleotide substitution is at any of positions 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26 within the [DH Domain].

19. The TREM of any one of the preceding claims, wherein the TREM comprises a nucleotide substitution within the [ACH Domain], e.g., the nucleotide substitution is at any of positions 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, or 43 within the [ACH Domain].

20. The TREM of any one of the preceding claims, wherein the TREM comprises a nucleotide substitution within the [VL Domain], e.g., the nucleotide substitution is at any of positions 44, 45, 46, 47, 48, or 49 within the [VL Domain],

21. The TREM of any one of the preceding claims, wherein the TREM comprises a nucleotide substitution within the [TH Domain], e.g., the nucleotide substitution is at any of positions 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, or 64 within the [TH Domain],

22. The TREM of any one of the preceding claims, wherein the TREM comprises a nucleotide substitution within the [ASt Domain2], e.g., the nucleotide substitution is at any of positions 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, or 76 within the [ASt Domain2],

23. The TREM of any one of the preceding claims, wherein the TREM has a sequence selected from a sequence provided in FIGs. 3 or 23.

24. The TREM of any one of the preceding claims, wherein the TREM comprises a plurality of nucleotide substitutions. 388 WO 2024/216206 PCT/US2024/024492

25. The TREM of any one of any one of the preceding claims, wherein the nucleotide substitution comprises substituting a first naturally occurring nucleotide with an adenosine, guanosine, cytosine, or uracil nucleotide.

26. The TREM of any one of the preceding claims, wherein the TREM is selected from SEQ IDNOs. 625-700, 701-800, 801-900, 901-1000, 1001-1100, 1101-1151, 1290-1300, 1301-1400, or 1401-1456 in FIG. 3.

27. The TREM of any one of the preceding claims, wherein the TREM comprising a nucleotide substitution does not exhibit a difference in a functional parameter from a TREM in FIGs. 3 or 23.

28. The TREM of any one of claims 1-26, wherein the TREM comprising a nucleotide substitution exhibits a difference in a functional parameter from a TREM in FIGs. 3 or 23.

29. The TREM of any one of the preceding claims, wherein the TREM comprising a nucleotide substitution exhibits an improvement in a functional parameter from a TREM in FIGs. or 23.

30. The TREM of any one of the preceding claims, wherein the improvement comprises an improvement of about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%. 45%, 50%. 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or greater, e.g., compared with the functional parameter of a TREM provided in FIGs. 3 or 23.

31. The TREM of any one of the preceding claims, wherein the TREM comprising a nucleotide substitution exhibits a reduction in a functional parameter from a TREM in FIGs. 3 or 23.

32. The TREM of any one of the preceding claims, wherein the reduction comprises a reduction of about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%. 45%, 50%. 55%, 60%, 65%, 389 WO 2024/216206 PCT/US2024/024492 70%, 75%, 80%, 85%, 90%, 95%, or greater, e.g., compared with the functional parameter of a TREM provided in FIGs. 3 or 23.

33. The TREM of any one of the preceding claims, wherein the TREM comprises a nucleotide substitution at any of positions 1, 2, 3, 4, 5, 6, or 7, e.g., within the [ASt Domainl].

34. The TREM of any one of the preceding claims, wherein the TREM comprises a nucleotide substitution at any of positions 16, 17, or 20a, e.g., within the [DH Domain],

35. The TREM of any one of the preceding claims, wherein the TREM comprises a nucleotide substitution at any of positions 27, 28, 29, 30, 31, 39, 40, 41, 42, or 43, e.g., within the [ACH Domain],

36. The TREM of any one of the preceding claims, wherein the TREM comprises a nucleotide substitution at any of positions 51, 59, 60, or 63, e.g., within the [TH Domain],

37. The TREM of any one of the preceding claims, wherein the TREM comprises a nucleotide substitution at any of positions 66, 67, 68, 69, 70, 71, 72, or 73, e.g., within the [ASt Domain2],

38. The TREM of any one of the preceding claims, wherein the TREM comprises a nucleotide substitution at any of positions 32, 33, 34, 35, 36, 37, or 38, e.g., within the [ACH Domain],

39. The TREM of any one of the preceding claims, wherein the TREM comprising a nucleotide substitution at any of positions 1, 2, 3, 4, 5, 6, or 7, e.g., within the [ASt Domainl], exhibits an improvement in a functional parameter of the TREM.

40. The TREM of any one of the preceding claims, wherein the TREM comprising a nucleotide substitution at any of positions 16, 17, or 20a, e.g., within the [DH Domain], exhibits an improvement in a functional parameter of the TREM. 390 WO 2024/216206 PCT/US2024/024492

41. The TREM of any one of the preceding claims, wherein the TREM comprising a nucleotide substitution at any of positions 27, 28, 29, 30, 31, 39, 40, 41, 42, or 43, e.g., within the [ACH Domain], exhibits an improvement in a functional parameter of the TREM.

42. The TREM of any one of the preceding claims, wherein the TREM comprising a nucleotide substitution at any of positions 51, 59, 60, or 63, e.g., within the [TH Domain], exhibits an improvement in a functional parameter of the TREM.

43. The TREM of any one of the preceding claims, wherein the TREM comprising a nucleotide substitution at any of positions 66, 67, 68, 69, 70, 71, 72, or 73, e.g., within the [ASt Domain2], exhibits an improvement in a functional parameter of the TREM

44. The TREM of any one of the preceding claims, wherein the TREM comprising a nucleotide substitution at any of positions 32, 33, 34, 35, 36, 37, or 38, e.g., within the [ACH Domain], exhibits a reduction in a functional parameter of the TREM

45. The TREM of any one of the preceding claims, wherein the TREM comprising a nucleotide substitution comprises a scaffold, e.g., an Arg-TGA, Gln-TAG, Glu-TAG, Leu-TAG, Tyr-TAG, Ser-TAG, or Lys-TAG scaffold, e.g., a TREM corresponding to a reference sequence ofSEQIDNO: 1638, 1835, 1660, 1654, 1867, 2000,2001,2016,2017, 2022, 2023,2020, 2021, 2018, or 2019.

46. The TREM of any one of the preceding claims, wherein the TREM comprising a nucleotide substitution corresponds to a reference sequence of SEQ ID NO: 1638, 1835, 1660, 1654, 1867, 2000, 2001, 2016, 2017, 2022, 2023, 2020, 2021, 2018, or 2019.

47. The TREM of any one of the preceding claims, wherein the TREM comprises a non- naturally occurring modification. 391 WO 2024/216206 PCT/US2024/024492

48. The TREM of claim 47, wherein the non-naturally occurring modification is present on the ?’-position of a nucleotide sugar or within the internucleotide region (e.g., a backbone modification).

49. The TREM of any one of claims 47-48, wherein the non-naturally occurring modification is selected from a 2’-O-methyl (2-OMe), 2’-halo (e.g., 2’F or 2’Cl), 2’-O-methoxyethyl (2’MOE), or 2‘deoxy modification.

50. The TREM of any one of claims 47-49, wherein the non-naturally occurring modification is a phosphorothioate modification.

51. The TREM of any one of claims 47-50, wherein the TREM comprises 1, 2, 3, 4, 5, 6, 7,8, 9, or 10 additional non-naturally occurring modifications compared with a TREM provided in FIG. 3 (e.g., 2’-ribose modifications or an internucleotide modification, e.g., 2’OMe, 2’-halo, 2’- MOE, 2’-deoxy, or phosphorothiorate modifications).

52. The TREM of any one of claims 47-51, wherein the TREM comprises a pattern of non- naturally occurring modifications selected from the patterns listed in Table 6.

53. The TREM of any one of the preceding claims, wherein:(i) the non-naturally occurring modification is present at a nucleotide position which corresponds to one or more of nucleotides 1-9 of SEQ ID NO; 734; and/or(ii) the TREM differs from the nucleotide sequence of SEQ ID NO: 734 by about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides.

54. The TREM of any one of the preceding claims, wherein:(i) the non-naturally occurring modification is present at a nucleotide position which corresponds to one or more of nucleotides 10-19 of SEQ ID NO: 734; and/or(ii) the TREM differs from the nucleotide sequence of SEQ ID NO: 734 by about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides. 392 WO 2024/216206 PCT/US2024/024492

55. The TREM of any one of the preceding claims, wherein:(i) the non-naturally occurring modification is present at a nucleotide position which corresponds to one or more of nucleotides 20-29 of SEQ ID NO: 734; and/or(ii) the TREM differs from the nucleotide sequence of SEQ ID NO: 734 by about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides.

56. The TREM of any one of the preceding claims, wherein:(i) the non-naturally occurring modification is present at a nucleotide position which corresponds to one or more of nucleotides 30-39 of SEQ ID NO: 734; and/or(ii) the TREM differs from the nucleotide sequence of SEQ ID NO: 734 by about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides.

57. The TREM of any one of the preceding claims, wherein;(i) the non-naturally occurring modification is present at a nucleotide position which corresponds to one or more of nucleotides 40-49 of SEQ ID NO: 734; and/or(ii) the TREM differs from the nucleotide sequence of SEQ ID NO; 734 by about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides.

58. The TREM of any one of the preceding claims, wherein;(i) the non-naturally occurring modification is present at a nucleotide position which corresponds to one or more of nucleotides 50-59 of SEQ ID NO: 734; and/or(ii) the TREM differs from the nucleotide sequence of SEQ ID NO: 734 by about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides.

59. The TREM of any one of the preceding claims, wherein:(i) the non-naturally occurring modification is present at a nucleotide position which corresponds to one or more of nucleotides 60-69 of SEQ ID NO: 734; and/or(ii) the TREM differs from the nucleotide sequence of SEQ ID NO: 734 by about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides.

60. The TREM of any one of the preceding claims, wherein: 393 WO 2024/216206 PCT/US2024/024492 (i) the non-naturally occurring modification is present at a nucleotide position which corresponds to one or more of nucleotides 70-76 of SEQ ID NO: 734; and/or(ii) the TREM differs from the nucleotide sequence of SEQ ID NO: 734 by about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides.

61. The TREM of any one of the preceding claims, wherein the non-naturally occurring modification is present at a nucleotide position which corresponds to one or more of nucleotides 1-76, according to the CtNS.

62. A pharmaceutical composition comprising a TREM of any one of the preceding claims.

63. The pharmaceutical composition of claim 90, further comprising a pharmaceutically acceptable component, e.g., an excipient.

64. A lipid nanoparticle formulation comprising a TREM of any one of claims 1-91.

65. A lipid nanoparticle formulation comprising a pharmaceutical composition of claim 92.

66. A composition for use in treating a subject having a disease or disorder associated with a PTC comprising administering to the subject a TREM described herein (e.g., a TREM of any one of the preceding claims).

67. The composition for use of claim 66, wherein the disease or disorder associated with a PTC comprises Hemophilia B, Fabry disease, Usher syndrome, or CLN2 disease.

68. A method of treating a subject having a disease or disorder associated with a PTC comprising administering to the subject a TREM described herein (e.g., a TREM of any one of the preceding claims), thereby treating the subject having the disease or disorder.

69. The method of claim 68, wherein the disease or disorder associated with a PTC comprises Hemophilia B, Fabry disease, Usher syndrome, or CLN2 disease. 394 WO 2024/216206 PCT/US2024/024492

70. A method of modulating a functional parameter of a tRNA effector molecule (TREM), wherein the TREM comprises a sequence of Formula (A):[Ll]x-[ASt Domain l]-[L2]x-[DH Domain]-[L3]x-[ACH Domain] -[VL Domain]-[THD0main]-[L4]x-[ASt D0main2]-[L5]x (A),wherein:independently, [Li] and [VL Domain], are optional;x is 0 or 1; andthe TREM comprises a nucleotide substitution (e.g., a nucleotide mutation) in the TREM capable of modulating a functional parameter of the TREM ;thereby modulating the functional parameter of the TREM. 395